Drug combinations containing PDE4 inhibitors and NSAIDs

ABSTRACT

Drug combinations which contain a PDE4-inhibitor and a non-steroidal anti-inflammatory drug (NSAID), processes for preparing them, and their use in treating in particular respiratory complaints such as COPD, chronic sinusitis, and asthma. The PDE4 inhibitors of the drug combinations include compounds of general formula 1 
                         
wherein X is SO or SO 2 , but preferably SO, R 3  is an optionally substituted, mono- or bicyclic, unsaturated, partly saturated or saturated heterocyclic group or an optionally substituted, mono- or bicyclic heteroaryl, and R 1  and R 2  have the meanings given in claim  1.

This application is a divisional of U.S. patent application Ser. No.13/201,262, filed Sep. 29, 2011, now U.S. Pat. No. 8,592,400, filed Sep.29, 2011, which issued Nov. 26, 2013, and which was the national phaseentry under 35 U.S.C. §371 of International Application No.PCT/EP2010/052077, filed Feb. 18, 2010, which claims priority toEurupean Patent Application Nos. 09153853.8, filed Feb. 27, 2009 and09166127.2, filed Jul. 22, 2009, the contents of all of which are herebyincorporated by reference in their entireties.

The present invention relates to new drug combinations which contain, inaddition to one or more PDE4-inhibitors, at least one NSAID(non-steroidal anti-inflammatory drug) (2), processes for preparing themand their use for treating in particular respiratory complaints such asfor example COPD, chronic sinusitis and asthma.

The invention relates particularly to those drug combinations whichcomprise, in addition to one or more, preferably one PDE4 inhibitor ofgeneral formula 1

wherein X is SO or SO₂, but preferably SO, R³ is an optionallysubstituted, mono- or bicyclic, unsaturated, partly saturated orsaturated heterocyclic group or an optionally substituted, mono- orbicyclic heteroaryl, and R¹ and R² have the meanings given in claim 1,at least one NSAID, the preparation thereof and use thereof for thetreatment of respiratory complaints.

PRIOR ART

EP 07118911.2 discloses heterocycle-substitutedpiperazino-dihydrothienopyrimidines of formula 1 as PDE4-inhibitors, thepreparation thereof and the use thereof for the treatment of respiratorycomplaints. It is also known that many “1st generation” PDE4-inhibitorssuch as rolipram, for example, lead to undesirable side effects.Consequently, it was an object of the present invention to provide adrug or drug combination containing a PDE4 inhibitor which has a lowside-effect profile.

DESCRIPTION OF THE INVENTION

Surprisingly it has now been found that drug combinations that—inaddition to a PDE4 inhibitor and in particular in addition to thedihydrothienopyrimidinesulphoxides of formula 1 known as PDE4-inhibitorswherein R³ denotes a mono- or bicyclic, unsaturated, partly saturated orsaturated heterocyclic group or a mono- or bicyclic heteroaryl (1)—alsocontain at least one NSAID (2), have a significantly lower PDE4-mediatedside effect profile compared with a drug that contains the correspondingPDE4 inhibitor or the corresponding dihydrothienopyrimidinesulphoxide offormula 1 on its own. Consequently, the dosage of the correspondingdihydrothienopyrimidinesulphoxide of formula 1 (as PDE4 inhibitor) mayturn out to be significantly higher, thus simultaneously increasing itseffectiveness in the treatment of for example respiratory complaintssuch as in particular COPD, chronic sinusitis and asthma whilesimultaneously retaining a low side effect profile. This therefore givesa larger therapeutic window for the PDE4 inhibitor used.

The present invention therefore relates to a novel drug combinationwhich contains, in addition to one or more PDE4-inhibitors, at least oneNSAID (=non-steroidal anti-inflammatory drug) (2).

The present invention preferably relates to drug combinations which, inaddition to one or more, preferably one compound of general formula 1 asPDE4 inhibitor

wherein

-   X denotes SO or SO₂,-   R¹ denotes H, C₁₋₆-alkyl,-   R² is H or a group selected from among C₁₋₁₀-alkyl and C₂₋₆-alkenyl,    which may optionally be substituted by one or more groups selected    from halogen and C₁₋₃-fluoroalkyl or which may optionally be    substituted by one or more groups selected from among OR^(2.1),    COOR^(2.1), CONR^(2.2)R^(2.3), SR^(2.1), SO—R^(2.1), SO₂—R^(2.1),    C₆₋₁₀-aryl, a het, a hetaryl, a mono- or bicyclic C₃₋₁₀-cycloalkyl,    CH₂—NR^(2.2)R^(2.3) and NR^(2.2)R^(2.3), which in turn may    optionally be substituted by one or more groups selected from among    OH, halogen, OR^(2.1), oxo, CF₃, CHF₂, CH₂F, C₁₋₆-alkyl,    C₁₋₆-alkanol, C₆₋₁₀-aryl, COOR^(2.1), CH₂—NR^(2.2)R^(2.3) and    NR^(2.2)R^(2.3),    -   wherein R^(2.1) is H or a group selected from among C₁₋₆-alkyl,        C₁₋₆-alkanol, C₁₋₃-haloalkyl, mono- or bicyclic C₃₄₀-cycloalkyl,        C₆₋₁₀-aryl-C₁₋₆-alkylene, mono- or bicyclic        hetaryl-C₁₋₆-alkylene, het-C₁₋₆-alkylene,        C₃₋₁₀-cycloalkyl-C₁₋₆-alkylene, a mono- or bicyclic C₆₋₁₀-aryl,        a hetaryl and a het, which may optionally be substituted by one        or more groups selected from among OH, O—(C₁₋₃-alkyl), halogen,        C₁₋₆-alkyl and C₆₋₁₀-aryl,    -   wherein R^(2.2) and R^(2.3) independently of one another denote        H or a group selected from among C₁₋₆-alkyl, mono- or bicyclic        C₃₋₁₀ cycloalkyl, C₆₋₁₀-aryl-C₁₋₆-alkylene,        hetaryl-C₁₋₆-alkylene, mono- or bicyclic C₆₋₁₀-aryl, het,        hetaryl, CO—NH₂, CO—NHCH₃, CO—N(CH₃)₂, SO₂—(C₁-C₂-alkyl),        CO—R^(2.1) and COOR^(2.1), which may optionally be substituted        by one or more groups selected from among OH, halogen,        C₁₋₆-alkyl, C₆₋₁₀-aryl and COOR^(2.1),        wherein-   het is a three- to eleven-membered, mono- or bicyclic, saturated or    partly saturated, optionally annelated or optionally bridged    heterocyclic group which contains 1, 2, 3 or 4 heteroatoms selected    independently of one another from among N, S or O, and wherein-   hetaryl is a five- to eleven-membered, mono- or bicyclic, optionally    annelated heteroaryl which contains 1, 2, 3 or 4 heteroatoms    selected independently of one another from among N, S or O, and    wherein-   cycloalkyl may be saturated or partly saturated, or-   R² denotes a mono- or polycyclic C₃₋₁₀ cycloalkyl, which may    optionally be singly or multiply bridged by C₁₋₃-alkyl groups and    which may optionally be substituted by a group selected from among    branched or unbranched C₁₋₆-alkanol, C₁₋₃-fluoroalkyl,    C₁₋₃-alkylene-OR^(2.1), OR^(2.1), COOR^(2.1), SO₂—NR^(2.2)R^(2.3),    het, C₆₋₁₀-aryl, C₁₋₆-alkyl, C₆₋₁₀-aryl-C₁₋₆-alkylene,    hetaryl-C₁₋₆-alkylene, mono- or bicyclic C₃₋₁₀ cycloalkyl and    NR^(2.2)R^(2.3), which may optionally be substituted by one or more    groups selected from among OH, OR^(2.1), oxo, halogen, CF₃, CHF₂,    CH₂F, C₁₋₆-alkyl, C₆₋₁₀-aryl and NR^(2.2)R^(2.3), or-   R² denotes a mono- or polycyclic C₆₋₁₀-aryl, which may optionally be    substituted by OH, SH or halogen or by one or more groups selected    from among OR^(2.1), COOR^(2.1), NR^(2.2)R^(2.3),    CH₂—NR^(2.2)R^(2.3), C₃₋₁₀-cycloalkyl, het, —C₁₋₆-alkyl,    C₁₋₃-fluoroalkyl, C₆₋₁₀-aryl-C₁₋₆-alkylene, het-C₁₋₆-alkylene,    hetaryl-C₁₋₆-alkylene, C₆₋₁₀-aryl, SO₂—CH₃, SO₂—CH₂CH₃ and    SO₂—NR^(2.2)R^(2.3), which in turn may optionally be substituted by    one or more groups selected from among OH, OR^(2.1), CF₃, CHF₂,    CH₂F, oxo, halogen, CF₃, CHF₂, CH₂F, C₁₋₆-alkyl, C₆₋₁₀-aryl and    NR^(2.2)R^(2.3), or-   R² denotes a group selected from among het and hetaryl, which may    optionally be substituted by one or more groups selected from among    halogen, OH, oxo, CF₃, CHF₂ and CH₂F or by one or more groups    selected from among OR^(2.1), C₁₋₃-alkylene-OR^(2.1), SR^(2.1),    SO—R^(2.1) and SO₂—R^(2.1), COOR^(2.1), COR^(2.1), C₁₋₆-alkanol,    C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, C₁₋₆-alkyl, C₆₋₁₀-aryl-C₁₋₆-alkylene,    hetaryl-C₁₋₆-alkylene, het, hetaryl, C₁₋₃-alkylene-OR^(2.1) and    NR^(2.2)R^(2.3), which in turn may optionally be substituted by one    or more groups selected from among OH, OR^(2.1), oxo, halogen, CF₃,    CHF₂, CH₂F, C₁₋₆-alkyl, C₆₋₁₀-aryl and NR^(2.2)R^(2.3), or wherein-   NR¹R² together denotes a heterocyclic four- to seven-membered ring    which may optionally be bridged, which contains 1, 2 or 3    heteroatoms selected from among N, O and S and which may optionally    be substituted by one or more groups selected from among OH,    OR^(2.1), C₁₋₃-alkylene-O^(R.1), oxo, halogen, C₁₋₆-alkyl,    C₆₋₁₀-aryl, COOR^(2.1), CH₂—NR^(2.2)—COO—R^(2.1),    CH₂—NR^(2.2)—CO—R^(2.1), CH₂—NR^(2.2)—CO—CH₂—NR^(2.2)R^(2.3),    CH₂—NR^(2.2)—SO₂—C₁₋₃-alkyl, CH₂—NR^(2.2)—SO₂—NR^(2.2)R^(2.3),    CH₂—NR^(2.2)—CO—NR^(2.2)R^(2.3), CO—NR^(2.2)R^(2.3),    CH₂—NR^(2.2)R^(2.3) and NR^(1.2)R^(2.3), and wherein-   R³ is a group selected from among a het and a hetaryl, which may    optionally be substituted by one or more groups selected from among    halogen, C₁₋₃-fluoroalkyl, CN, OH, oxo, —C₁₋₆-alkyl, —O—R^(2.1),    —COOR^(2.1), SO—R^(2.1), SO₂—R^(2.1), C₆₋₁₀-aryl,    C₁₋₃-alkylene-C₆₋₁₀-aryl, —C₁₋₃-alkylene-NR^(2.2)R^(2.3),    —NR^(2.2)R^(2.3), a C₃₋₁₀-cycloalkyl, a    C₁₋₃-alkylene-C₃₋₁₀-cycloalkyl, a het, a hetaryl,    C₁₋₃-alkylene-hetaryl, and C₁₋₃-alkylene-het, which in turn may    optionally be substituted by one or more groups selected from among    OH, halogen, —C₁₋₃-fluoroalkyl, C₆₋₁₀-aryl, —COO(C₁₋₃-alkyl) and    O—(C₁₋₃-alkyl),    contain at least one NSAID (=non-steroidal anti-inflammatory drug)    (2).

Preferred are drug combinations which, in addition to one or more,preferably one, compound of general formula 1 as PDE4 inhibitor, wherein

-   X denotes SO,-   R¹ denotes H-   R² is H or C₁₋₆-alkyl, which may optionally be substituted by one or    more groups selected from F, CF₃, CHF₂ or CH₂F or which may    optionally be substituted by one or more groups selected from among    OR^(2.1), COOR^(2.1), CONR^(2.2)R^(2.3), SR^(2.1), SO—R^(2.1),    SO₂—R^(2.1), phenyl, a het, a hetaryl, a monocyclic C₃₋₇-cycloalkyl,    CH₂—NR^(2.2)R^(2.3) and NR^(2.2)R^(2.3), which in turn may    optionally be substituted by one or more groups selected from among    OH, F, Cl, Br, CF₃, CHF₂, CH₂F, OR^(2.1), oxo, methyl, ethyl,    propyl, isopropyl, C₁₋₂-alkanol, phenyl, COOR^(2.1),    CH₂—NR^(2.2)R^(2.3) and NR^(2.2)R^(2.3),    -   wherein R^(2.1) is H or a group selected from among methyl,        ethyl, propyl, isopropyl, monocyclic C₃₋₇ cycloalkyl,        phenyl-C₁₋₂-alkylene, hetaryl-C₁₋₂-alkylene, het-C₁₋₂-alkylene,        C₃₋₇-cycloalkyl-C₁₋₂-alkylene, phenyl, a hetaryl and a het,        which may optionally be substituted by one or more groups        selected from among OH, halogen, methyl, ethyl, propyl,        isopropyl, O-methyl, O-ethyl, O-propyl, O-isopropyl and phenyl,    -   wherein R^(2.2) and R^(2.3) independently of one another denote        H or a group selected from among methyl, ethyl, propyl,        isopropyl, monocyclic C₃₋₇ cycloalkyl, phenyl-C₁₋₃-alkylene,        hetaryl-C₁₋₃-alkylene, phenyl, het, hetaryl, CO—NH₂, CO—NHCH₃,        CON(CH₃)₂, SO₂—(C₁-C₂-alkyl), CO—R^(2.1) and COOR^(2.1), which        may optionally be substituted by one or more groups selected        from among OH, F, Cl, Br, methyl, ethyl, propyl, isopropyl,        phenyl and COOR^(2.1),        wherein-   het is a three- to seven-membered, monocyclic, saturated or partly    saturated heterocyclic group which contains 1, 2 or 3 heteroatoms    independently selected from among N, S or O, and wherein-   hetaryl is a five- to six-membered, monocyclic, aromatic heteroaryl    which contains 1, 2 or 3 heteroatoms independently selected from    among N, S or O, and wherein-   cycloalkyl may be saturated or partly saturated, or-   R² denotes a monocyclic C₃₋₇ cycloalkyl, which may optionally be    substituted by a group selected from among branched or unbranched    C₁₋₂-alkanol, C₁₋₃-fluoroalkyl, C₁₋₃-alkylene-OR^(2.1), OR^(2.1),    COOR^(2.1), SO₂—NR^(2.2)R^(2.3), het, methyl, ethyl, propyl,    isopropyl, phenyl, phenyl-C₁₋₂-alkylene, hetaryl-C₁₋₂-alkylene,    monocyclic C₃₋₇ cycloalkyl and NR^(2.2)R^(2.3), which may optionally    be substituted by one or more groups selected from among OH,    OR^(2.1), oxo, halogen, CF₃, CHF₂, CH₂F, methyl, ethyl, propyl,    isopropyl, phenyl and NR^(2.2)R^(2.3), or-   R² denotes a phenyl, which may optionally be substituted by OH, SH,    F, Cl or Br or by one or more groups selected from among OR^(2.1),    COOR^(2.1), CH₂—NR^(2.2)R^(2.3), C₃₋₇-cycloalkyl, het, methyl,    ethyl, propyl, isopropyl, CF₃, CHF₂, CH₂F, phenyl-C₁₋₂-alkylene,    het-C₁₋₂-alkylene, hetaryl-C₁₋₂-alkylene, phenyl, SO₂—CH₃,    SO₂—CH₂CH₃ and SO₂—NR^(2.2)R^(2.3), which in turn may optionally be    substituted by one or more groups selected from among OH, OR^(2.1),    oxo, F, Cl, Br, CF₃, CHF₂, CH₂F, methyl, ethyl, propyl, isopropyl,    phenyl and NR^(2.2)R^(2.3), or-   R² denotes a group selected from among a het and a hetaryl, which    may optionally be substituted by one or more groups selected from    among F, Cl, Br, OH, oxo, CF₃, CHF₂, CH₂F and SH or by one or more    groups selected from among OR^(2.1), C₁₋₃-alkylene-OR^(2.1),    SR^(2.1)SO—R^(2.1), SO—R^(2.1), SO₂—R^(2.1), COOR^(2.1), COR^(2.1),    C₁₋₂-alkanol, C₃₋₁₀-cycloalkyl, phenyl, methyl, ethyl, propyl,    isopropyl, phenyl-C₁₋₂-alkylene, hetaryl-C₁₋₂-alkylene, het,    hetaryl, C₁₋₂-alkanol and NR^(2.2)R^(2.3), which in turn may    optionally be substituted by one or more groups selected from among    OH, OR^(2.1), oxo, F, Cl, Br, CF₃, CHF₂, CH₂F, C₁₋₆-alkyl, phenyl    and NR^(2.2)R^(2.3), and wherein-   R³ is a group selected from among a saturated or partly saturated,    monocyclic three- to seven-membered heterocyclic group, a saturated    or partly saturated, bicyclic five- to eleven-membered heterocyclic    group, a monocyclic, five- to six-membered heteroaryl and a    bicyclic, seven- to eleven-membered heteroaryl, which contains in    each case 1, 2, 3 or 4 heteroatoms selected independently of one    another from among N, O and S and which may optionally be    substituted in each case by one or more groups selected from among    halogen, C₁₋₃-fluoroalkyl, CN, OH, oxo, —C₁₋₆-alkyl, —COOR^(2.1),    SO—R^(2.1), SO₂—R^(2.1), C₆₋₁₀-aryl, C₁₋₃-alkylene-C₆₋₁₀-aryl,    —C₁₋₃-alkylene-NR^(2.2)R^(2.3), —NR^(2.2)R^(2.3), a    C₃₋₁₀-cycloalkyl, a C₁₋₃-alkylene-C₃₋₁₀-cycloalkyl, het, a hetaryl,    C₁₋₃-alkylene-hetaryl and C₁₋₃-alkylene-het, which in turn may    optionally be substituted by one or more groups selected from among    OH, halogen, —C₁₋₃-fluoroalkyl, C₁₋₆-alkyl, C₆₋₁₀-aryl,    —COO(C₁₋₃-alkyl) and O—(C₁₋₃-alkyl),    contain at least one NSAID (2).

Also preferred are drug combinations which, in addition to one or more,preferably one, compound of general formula 1 as PDE4 inhibitor, wherein

-   R² is a group according to formula 3

-   wherein R⁵ is OH or NH₂ and-   wherein R⁴ denotes a group selected from among C₁₋₄-alkyl, hetaryl    and phenyl, which may optionally be substituted by one or more    groups selected from among OH, F, Br, OR^(2.1), oxo, methyl, ethyl,    C₁₋₂-alkanol, phenyl, COOR^(2.1), CH₂—NR^(2.2)R^(2.3) and    NR^(2.2)R^(2.3), and wherein the remaining groups are as    hereinbefore defined,    contain at least one NSAID (2).

Also preferred are drug combinations which, in addition to one or more,preferably one, compound of general formula 1 as PDE4 inhibitor, wherein

-   R² is a group according to formula 3

-   wherein R⁵ is OH or NH₂ and-   wherein R⁴ denotes methyl, ethyl, propyl, isopropyl-   and wherein the remaining groups are as hereinbefore defined,    contain at least one NSAID (2).

Also preferred are drug combinations which, in addition to one or more,preferably one, compound of general formula 1 as PDE4 inhibitor, wherein

R² is a monocyclic three-, four-, five-, six- or seven-memberedcycloalkyl ring which may optionally be substituted in the spiroposition by a group selected from among —CH₂—OR^(2.1), branched orunbranched C₂₋₆-alkylene-OR^(2.1), methyl, ethyl, propyl, isopropyl,butyl, isobutyl, cyclopropyl, —CF₃, CHF₂, CH₂F and C₂₋₄-fluoroalkyl,wherein R^(2.1) is selected from among methyl, ethyl, propyl, isopropyl,butyl, isobutyl, and wherein the remaining groups are as hereinbeforedefined, contain at least one NSAID (2).

Also preferred are drug combinations which, in addition to one or more,preferably one, compound of general formula 1 as PDE4 inhibitor, wherein

R² is a phenyl which is optionally substituted in one or both metapositions by one or more groups selected from among methyl, ethyl,propyl, isopropyl, cyclopropyl, F, Cl, Br, OH, OR^(2.1), COOR^(2.1),CF₃, CHF₂, CH₂F, NH₂ and N(CH₃)₂, wherein R^(2.1) may be H, methyl orethyl,

and wherein the remaining groups are as hereinbefore defined, contain atleast one NSAID (2).

Also preferred are drug combinations which, in addition to one or more,preferably one, compound of general formula 1 as PDE4 inhibitor, wherein

-   R² is a monocyclic, saturated three-, four-, five-, six- or    seven-membered heterocyclic group with 1, 2 or 3 heteroatoms in each    case selected from among N, O and S, which may optionally be    substituted by one or more groups selected from among fluorine,    chlorine, bromine, CF₃, CHF₂, CH₂F, OH, oxo and SH or by one or more    groups selected from among OR^(2.1,) C₁₋₃-alkylene-OR^(2.1),    SR^(2.1), SO—R^(2.1), SO₂—R^(2.1), COOR^(2.1), COR^(2.1),    C₁₋₆-alkanol, C₃₋₁₀-cycloalkyl, phenyl, C₁₋₆-alkyl,    phenyl-C₁₋₆-alkylene, hetaryl-C₁₋₆-alkylene, het, hetaryl and    NR^(2.2)R^(2.3), which in turn may optionally be substituted by one    or more groups selected from among OH, OR^(2.1), oxo, F, Cl, CF₃,    CHF₂, CH₂F, C₁₋₆-alkyl, phenyl and NR^(2.2)R^(2.3), wherein R^(2.1),    R^(2.2) and R^(2.3) and the remaining groups are as hereinbefore    defined,    contain at least one NSAID (2).

Also preferred are drug combinations which, in addition to one or more,preferably one, compound of general formula 1 as PDE4 inhibitor, wherein

-   R² is a monocyclic, saturated, six-membered heterocyclic group with    a heteroatom selected from among N, O and S, which may optionally be    substituted by one or more groups selected from among F, Cl, Br,    CF₃, CHF₂, CH₂F, OH, oxo, NH₂, NHCH₃, N(CH₃)₂, methyl, ethyl,    propyl, isopropyl, cyclopropyl, methoxy and ethoxy, and wherein the    remaining groups are as hereinbefore defined,    contain at least one NSAID (2).

Also preferred are drug combinations which, in addition to one or more,preferably one, compound of general formula 1 as PDE4 inhibitor, wherein

-   R² denotes a group selected from among piperidine or    tetrahydropyran, which may optionally be substituted by one or more    groups selected from among F, Cl, Br, OH, CF₃, CHF₂, CH₂F, NH₂,    NHCH₃, N(CH₃)₂, oxo, methyl and methoxy, and wherein the remaining    groups are as hereinbefore defined,    contain at least one NSAID (2).

Also preferred are drug combinations which, in addition to one or more,preferably one, compound of general formula 1 as PDE4 inhibitor, wherein

-   R³ is a monocyclic five- or six-membered heteroaryl ring which may    optionally be substituted by one or more groups selected from among    F, Cl, Br, CF₃, CHF₂, CH₂F, CN, OH, —methyl, ethyl, propyl,    isopropyl, —O-methyl, O-ethyl, —COOmethyl, —COOethyl, SO₂—(CH₃),    SO—(CH₃), SO₂—(CH₂CH₃), SO—(CH₂CH₃), phenyl, -methylene-phenyl,    -ethylene-phenyl, —NH₂, —NH(CH₃), N(CH₃)₂, -methylene-NH₂,    -methylene-NH(CH₃), -methylene-N(CH₃)₂, a C₃₋₆-cycloalkyl, a    methylene-C₃₋₆-cycloalkyl, a saturated or partly saturated, five- to    six-membered heterocyclic group, a five- or six-membered heteroaryl,    -methylene-hetaryl, and -methylene-het, which in turn may optionally    be substituted by one or more groups selected from among OH, F, Cl,    Br, CF₃, CHF₂, CH₂F, methyl, ethyl, propyl, isopropyl, phenyl,    —COO(CH₃), —O-methyl and —O-ethyl, and wherein the remaining groups    are as hereinbefore defined,    contain at least one NSAID (2).

Also preferred are drug combinations which, in addition to one or more,preferably one, compound of general formula 1 as PDE4 inhibitor, wherein

-   R³ is a bicyclic 9- to 11-membered saturated, unsaturated or partly    saturated heterocyclic group which may optionally be substituted by    one or more groups selected from among    -   F, Cl, Br, CF₃, CHF₂, CH₂F, CN, OH, -methyl, ethyl, propyl,        isopropyl, —O-methyl, O-ethyl, —COOmethyl, —COOethyl, SO₂—(CH₃),        SO—(CH₃), SO₂—(CH₂CH₃), SO—(CH₂CH₃), phenyl, -methylene-phenyl,        -ethylene-phenyl, —NH2, —NH(CH₃), N(CH₃)₂, -methylene-NH₂,        -methylene-NH(CH₃), -methylene-N(CH₃)₂, a —C₃₋₆-cycloalkyl, a        -methylene-C₃₋₆-cycloalkyl, a saturated, partly unsaturated or        unsaturated 5- to 6-membered heterocyclic group, a 5- to        6-membered heteroaryl, -methylene-hetaryl, and -methylene-het,        which in turn may optionally be substituted by one or more        groups selected from among OH, F, Cl, Br, CF₃, CHF₂, CH₂F,        methyl, ethyl, propyl, isopropyl, phenyl, —COO(CH₃), —O-methyl        and —O-ethyl, and wherein the remaining groups are as        hereinbefore defined,        contain at least one NSAID (2).

Also preferred are drug combinations which, in addition to one or more,preferably one, compound of general formula 1 as PDE4 inhibitor, wherein

-   R³ is a monocyclic five- or six-membered heteroaryl ring selected    from among pyrrole, pyrazole, furan, thiophene, thiazole, imidazole,    oxazole, pyridazine, pyrimidine, pyrazine, thiadiazole, oxadiazole,    triazine, isoxazole, isothiazole and pyridine, which may optionally    be substituted by one or more groups selected from among F, Cl, Br,    CF₃, CHF₂, CH₂F, CN, OH, -methyl, ethyl, propyl, isopropyl,    —O-methyl, O-ethyl, —COOmethyl, —COOethyl, SO₂—(CH₃), SO₂—(CH₂CH₃),    phenyl, -methylene-phenyl, -ethylene-phenyl, —NH₂, —NH(CH₃),    N(CH₃)₂, -methylene-NH₂, -methylene-NH(CH₃), -methylene-N(CH₃)₂, a    C₃₋₆-cycloalkyl, a methylene-C₃₋₆-cycloalkyl, a het, a hetaryl,    -methylene-hetaryl, and -methylene-het, which in turn may optionally    be substituted by one or more groups selected from among OH, F, Cl,    Br, CF₃, CHF₂, CH₂F, methyl, ethyl, propyl, isopropyl, phenyl,    —COO(CH₃), —O-methyl and —O-ethyl, and wherein the remaining groups    are as hereinbefore defined,    contain at least one NSAID (2).

Also preferred are drug combinations which, in addition to one or more,preferably one, compound of general formula 1 as PDE4 inhibitor, wherein

-   R³ denotes a bicyclic 9- to 11-membered heterocyclic group selected    from among benzoxazole, benzodioxole, dihydrobenzodioxin,    benzodioxin, benzisoxazole, benzothiazole, benzisothiazole,    thienopyrimidine, furopyrimidine, thienopyridine, furopyridine,    indole, isoindole, quinoxaline, naphthyridine, pyridopyrazine,    pyridopyrimidine, quinoline, isoquinoline, benzoimidazole,    6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine, benzothiophene,    benzofuran, quinazoline, indazole, isobenzofuran and pteridine,    which may optionally be substituted by one or more groups selected    from among F, Cl, Br, CF₃, CHF₂, CH₂F, CN, OH, -methyl, ethyl,    propyl, isopropyl, —O-methyl, O-ethyl, —COOmethyl, —COOethyl,    SO₂—(CH₃), SO₂—(CH₂CH₃), phenyl, -methylene-phenyl,    -ethylene-phenyl, —NH₂, —NH(CH₃), N(CH₃)₂, -methylene-NH₂,    -methylene-NH(CH₃), -methylene-N(CH₃)₂, a C₃₋₆-cycloalkyl, a    methylene-C₃₋₆-cycloalkyl, a het, a hetaryl, -methylene-hetaryl, and    -methylene-het, which in turn may optionally be substituted by one    or more groups selected from among OH, F, Cl, Br, CF₃, CHF₂, CH₂F,    methyl, ethyl, propyl, isopropyl, phenyl, —COO(CH₃), —O-methyl and    —O-ethyl, and wherein the remaining groups are as hereinbefore    defined,    contain at least one NSAID (2).

Also preferred are drug combinations which, in addition to one or more,preferably one, compound of general formula 1 as PDE4 inhibitor, wherein

-   R¹ is H,-   R² is a group selected from among

-   R³ is a group selected from among

contain at least one NSAID (2).

Also preferred are drug combinations which, in addition to one or more,preferably one, compound of general formula 1 as PDE4 inhibitor selectedfrom among:

-   1.1    (3-fluorophenyl)-[5-oxo-2-(4-thiazol-2-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-amine-   1.2    (R)-3-methyl-2-[5-oxo-2-(4-thiazol-2-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-butan-1-ol-   1.3    [2-(4-benzoxazol-2-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5λ□⁴-thieno[3,2-d]pyrimidin-4-yl]-(3-fluorophenyl)-amine-   1.4    [2-(4-benzoxazol-2-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-(tetrahydropyran-4-yl)-amine-   1.5    (R)-2-{2-[4-(6-chloropyridazin-3-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-3-methylbutan-1-ol-   1.6    {2-[4-(6-chloropyridazin-3-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-(3-fluorophenyl)-amine-   1.7    (R)-2-[2-(4-benzoxazol-2-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-3-methylbutan-1-ol-   1.8    (1-{2-[4-(5-chloropyridin-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-cyclopropyl)-methanol-   1.9    {2-[4-(5-chloropyridin-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-(tetrahydropyran-4-yl)-amine-   1.10    {2-[4-(3-dimethylaminopyridazin-4-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-(3-fluorophenyl)-amine-   1.11    6-chloro-4-{4-[4-(3-fluorophenylamino)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-2-yl]-piperazin-1-yl}-pyridazin-3-ol-   1.12    2-{4-[6-(2-ethoxyethoxy)-pyridazin-3-yl]-piperazin-1-yl}-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl)-(3-fluorophenyl)-amine-   1.13    (3-fluorophenyl)-[5-oxo-2-(4-pyridazin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-amine-   1.14    (R)-2-{2-[4-(4-methoxy-1-methyl-1H-benzimidazol-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-3-methylbutan-1-ol-   1.15    (R)-2-{2-[4-(7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepin-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-3-methylbutan-1-ol-   1.16    (R)-3-methyl-2-[5-oxo-2-(4-pyrimidin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-butan-1-ol-   1.17    4-{4-[4-((R)-1-hydroxymethyl-2-methylpropylamino)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-2-yl]-piperazin-1-yl}-pyridin-2-ol-   1.18    (R)-3-methyl-2-[5-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-butan-1-ol-   1.19    (R)-2-{2-[4-(3-dimethylaminopyridazin-4-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-3-methylbutan-1-ol-   1.20    6-chloro-4-{4-[4-((R)-1-hydroxymethyl-2-methylpropylamino)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-2-yl]-piperazin-1-yl}-pyridazin-3-ol-   1.21    (R)-2-(2-{4-[6-(2-ethoxyethoxy)-pyridazin-3-yl]-piperazin-1-yl}-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino)-3-methylbutan-1-ol-   1.22    (R)-3-methyl-2-[5-oxo-2-(4-pyridazin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-butan-1-ol-   1.23    {1-[5-oxo-2-(4-pyrimidin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-cyclopropyl}-methanol-   1.24    {1-[5-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-cyclopropyl}-methanol-   1.25    (S)-1-methyl-5-[5-oxo-2-(4-pyrimidin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-piperidin-2-one-   1.26    {2-[4-(5-fluoro-1-methyl-1H-benzimidazol-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-(tetrahydropyran-4-yl)-amine-   1.27    [5-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-(tetrahydropyran-4-yl)-amine-   1.28    (3-fluorophenyl)-{2-[4-(4-methoxy-1-methyl-1H-benzimidazol-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-amine-   1.29    {2-[4-(7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepin-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-(3-fluorophenyl)-amine-   1.30    (3-fluorophenyl)-[5-oxo-2-(4-pyrimidin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-amine-   1.31    4-{4-[4-(3-fluorophenylamino)-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-2-yl]-piperazin-1-yl}-pyridin-2-ol-   1.32    (3-fluorophenyl)-[5-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl]-amine-   1.33    (3-fluorophenyl)-(2-{4-[4-(4-fluorophenyl)-thiazol-2-yl]-piperazin-1-yl}-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl)-amine-   1.34    [2-(4-benzo[d]isoxazol-3-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl]-(3-fluorophenyl)-amine-   1.35    (R)-2-(2-{4-[4-(4-fluorophenyl)-thiazol-2-yl]-piperazin-1-yl}-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-ylamino)-3-methylbutan-1-ol-   1.36    (R)-2-[2-(4-benzo[d]isoxazol-3-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-ylamino]-3-methylbutan-1-ol    contain at least one NSAID (2).

The above mentioned compounds of formula 1 are prepared as described indetail in the synthesis instructions.

Also preferred are the above drug combinations which contain at leastone NSAID (a) selected from COX 1-inhibitors or COX 2-inhibitors, inaddition to one or more, preferably one, compound of general formula 1as PDE4 inhibitor.

Also preferred are the above mentioned drug combinations which contain,in addition to one or more, preferably one compound of general formula 1as PDE4 inhibitor, at least one NSAID (2) selected from amongaceclofenac (2.1), acemetacin (2.2), acetylsalicylic acid (2.3),alclofenac (2.4), alminoprofen (2.5), amfenac (2.6), ampiroxicam (2.7),antolmetinguacil (2.8), anirolac (2.9), antrafenine (2.10), azapropazone(2.11), benorilate (2.12), bermoprofen (2.13), bindarit (2.14),bromfenac (2.15), bucloxinic acid (2.16), bucolom (2.17), bufexamac(2.18), bumadizone (2.19), butibufen (2.20), butixirate (2.21),carbasalate calcium (2.22), carprofen (2.23), choline magnesiumtrisalicylate (2.24), celecoxib (2.25), cinmetacin (2.26), cinnoxicam(2.27), clidanac (2.28), clobuzarit (2.29), deboxamet (2.30),dexibuprofen (2.31), dexketoprofen (2.32), diclofenac (2.33), diflunisal(2.34), droxicam (2.35), eltenac (2.36), enfenamic acid (2.37),etersalate (2.38), etodolac (2.39), etofenamat (2.40), etoricoxib(2.41), feclobuzon (2.42), felbinac (2.43), fenbufen (2.44), fenclofenac(2.45), fenoprofen (2.46), fentiazac (2.47), fepradinol (2.48),feprazone (2.49), flobufen (2.50), floctafenin (2.51), flufenamic acid(2.52), flufenisal (2.53), flunoxaprofen (2.54), flurbiprofen (2.55),flurbiprofenaxetil (2.56), furofenac (2.57), furprofen (2.58),glucametacin (2.59), ibufenac (2.60), ibuprofen (2.61), indobufen(2.62), indometacin (2.63), indometacinfarnesil (2.64), indoprofen(2.65), isoxepac (2.66), isoxicam (2.67), ketoprofen (2.68), ketorolac(2.69), lobenzarit (2.70), lonazolac (2.71), lornoxicam (2.72),loxoprofen (2.73), lumiracoxib (2.74), meclofenamic acid (2.75),meclofen, mefenamic acid (2.76), meloxicam (2.77), mesalazin (2.78),miroprofen (2.79), mofezolac (2.80), nabumetone (2.81), naproxen (2.82),nifluminic acid (2.83), olsalazine (2.84), oxaprozin (2.85), oxipinac(2.86), oxyphenbutazone (2.87), parecoxib (2.88), phenylbutazone (2.89),pelubiprofen (2.90), pimeprofen (2.91), pirazolac (2.92), priroxicam(2.93), pirprofen (2.94), pranoprofen (2.95), prifelon (2.96), prinomod(2.97), proglumetacin (2.98), proquazone (2.99), protizinic acid(2.100), rofecoxib (2.101), romazarit (2.102), salicylamide (2.103),salicylic acid (2.104), salmistein (2.105), salnacedin (2.106),salsalate (2.107), sulindac (2.108), sudoxicam (2.109), suprofen(2.110), talniflumat (2.111), tenidap (2.112), tenosal (2.113),tenoxicam (2.114), tepoxalin (2.115), tiaprofenic acid (2.116), taramide(2.117), tilnoprofenarbamel (2.118), timegadine (2.119), tinoridine(2.120), tiopinac (2.121), tolfenamic acid (2.122), tolmetin (2.123),ufenamate (2.124), valdecoxib (2.125), ximoprofen (2.126), zaltoprofen(2.127) and zoliprofen (2.128).

Also preferred are the above drug combinations which contain, inaddition to one or more, preferably one PDE4 inhibitor of generalformula 1, as NSAID (a) at least one COX 2 inhibitor selected from amongcelecoxib (2.25), etoricoxib (2.41), lumiracoxib (2.74), parecoxib(2.88), rofecoxib (2.101) and valdecoxib (2.125).

Particularly preferred are the above-mentioned drug combinations whichcontain, in addition to one or more, preferably one PDE4 inhibitor ofgeneral formula L at least one NSAID (1) selected from amongacetylsalicylic acid (2.3), celecoxib (2.25), diclofenac (2.33),ibuprofen (2.61), indometacin (2.63), lumiracoxib (2.74), meloxicam(2.77), naproxen (2.82) and priroxicam (2.93).

The present invention relates in particular to the above-mentioned drugcombinations which contain, in addition to one or more, preferably onePDE4 inhibitor of general formula 1, at least one NSAID (1) selectedfrom among acetylsalicylic acid (2.3), diclofenac (2.33), meloxicam(2.77), naproxen (2.82) and ibuprofen (2.61).

Particularly preferred within the scope of the present invention arethose of the above drug combinations which are selected from among 1.1and 2.3; 1.1 and 2.33; 1.1 and 2.77; 1.1 and 2.82; 1.1 and 2.61; 1.2 and2.3; 1.2 and 2.33; 1.2 and 2.77; 1.2 and 2.82; 1.2 and 2.61; 1.3 and2.3; 1.3 and 2.33; 1.3 and 2.77; 1.3 and 2.82; 1.3 and 2.61; 1.4 and2.3; 1.4 and 2.33; 1.4 and 2.77; 1.4 and 2.82; 1.4 and 2.61; 1.5 and2.3; 1.5 and 2.33; 1.5 and 2.77; 1.5 and 2.82; 1.5 and 2.61; 1.6 and2.3; 1.6 and 2.33; 1.6 and 2.77; 1.6 and 2.82; 1.6 and 2.61; 1.7 and2.3; 1.7 and 2.33; 1.7 and 2.77; 1.7 and 2.82; 1.7 and 2.61; 1.8 and2.3; 1.8 and 2.33; 1.8 and 2.77; 1.8 and 2.82; 1.8 and 2.61; 1.9 and2.3; 1.9 and 2.33; 1.9 and 2.77; 1.9 and 2.82; 1.9 and 2.61; 1.10 and2.3; 1.10 and 2.33; 1.10 and 2.77; 1.10 and 2.82; 1.10 and 2.61; 1.11and 2.3; 1.11 and 2.33; 1.11 and 2.77; 1.11 and 2.82; 1.11 and 2.61;1.12 and 2.3; 1.12 and 2.33; 1.12 and 2.77; 1.12 and 2.82; 1.12 and2.61; 1.13 and 2.3; 1.13 and 2.33; 1.13 and 2.77; 1.13 and 2.82; 1.13and 2.61; 1.14 and 2.3; 1.14 and 2.33; 1.14 and 2.77; 1.14 and 2.82;1.14 and 2.61; 1.15 and 2.3; 1.15 and 2.33; 1.15 and 2.77; 1.15 and2.82; 1.15 and 2.61; 1.16 and 2.3; 1.16 and 2.33; 1.16 and 2.77; 1.16and 2.82; 1.16 and 2.61; 1.17 and 2.3; 1.17 and 2.33; 1.17 and 2.77;1.17 and 2.82; 1.17 and 2.61; 1.18 and 2.3; 1.18 and 2.33; 1.18 and2.77; 1.18 and 2.82; 1.18 and 2.61; 1.19 and 2.3; 1.19 and 2.33; 1.19and 2.77; 1.19 and 2.82; 1.19 and 2.61; 1.20 and 2.3; 1.20 and 2.33;1.20 and 2.77; 1.20 and 2.82; 1.20 and 2.61; 1.21 and 2.3; 1.21 and2.33; 1.21 and 2.77; 1.21 and 2.82; 1.21 and 2.61; 1.22 and 2.3; 1.22and 233; 1.22 and 2.77; 1.22 and 2.82; 1.22 and 2.61; 1.23 and 2.3; 1.23and 233; 1.23 and 2.77; 1.23 and 2.82; 1.23 and 2.61; 1.24 and 2.3; 1.24and 2.33; 1.24 and 2.77; 1.24 and 2.82; 1.24 and 2.61; 1.25 and 2.3;1.25 and 2.33; 1.25 and 2.77; 1.25 and 2.82; 1.25 and 2.61; 1.26 and2.3; 1.26 and 2.33; 1.26 and 2.77; 1.26 and 2.82; 1.26 and 2.61; 1.27and 2.3; 1.27 and 2.33; 1.27 and 2.77; 1.27 and 2.82; 1.27 and 2.61;1.28 and 2.3; 1.28 and 2.33; 1.28 and 2.77; 1.28 and 2.82; 1.28 and2.61; 1.29 and 2.3; 1.29 and 2.33; 1.29 and 2.77; 1.29 and 2.82; 1.29and 2.61; 1.30 and 2.3; 1.30 and 2.33; 1.30 and 2.77; 1.30 and 2.82;1.30 and 2.61; 1.31 and 2.3; 1.31 and 2.33; 1.31 and 2.77; 1.31 and2.82; 1.31 and 2.61; 1.32 and 2.3; 1.32 and 2.33; 1.32 and 2.77; 1.32and 2.82; 1.32 and 2.61; 1.33 and 2.3; 1.33 and 2.33; 1.33 and 2.77;1.33 and 2.82; 1.33 and 2.61; 1.34 and 2.3; 1.34 and 2.33; 1.34 and2.77; 1.34 and 2.82; 1.34 and 2.61; 1.35 and 2.3; 1.35 and 2.33; 1.35and 2.77; 1.35 and 2.82; 1.35 and 2.61; 1.36 and 2.3; 1.36 and 2.33;1.36 and 2.77; 1.36 and 2.82; 1.36 and 2.61.

Particularly preferred are the above-mentioned drug combinations whereinthe PDE4 inhibitor of general formula 1 is administered in a single doseof 0.01 mg to 50 mg, preferably 0.05 to 30 mg, more preferably 0.1 to 20mg, particularly 0.5 to 10 mg.

Also particularly preferred are the above mentioned drug combinations,wherein the NSAID (2) used is either

-   -   acetylsalicylic acid (2.3) in a single dose of 50 to 2000 mg,        preferably 100 to 500 mg,    -   diclofenac (2.33) in a single dose of 25 mg to 150 mg,        preferably 25 to 100 mg,    -   meloxicam (2.77) in a single dose of 7.5 mg to 30 mg, preferably        10 to 20 mg,    -   naproxen in a single dose of 250 to 1000 mg, preferably 250 to        750 mg, or    -   ibuprofen in a single dose of 200 to 2400 mg, preferably 200 to        800 mg,        this single dose in each case being given once or twice a day.

In particular the invention relates to the above mentioned drugcombinations, wherein the or at least one or more of the PDE4inhibitor-mediated side effects is considerably reduced or avoidedcompletely by comparison with the sole administration of the PDE4inhibitor used in the drug combination. These PDE4 inhibitor-mediatedside effects are preferably selected from among weight loss,leukocytosis, neutrophilia, nausea, vomiting, diarrhoea (including theoccurrence of inflammatory parameters and the proliferation offibroblasts in the mesentery). These PDE4 inhibitor-mediated sideeffects are more preferably selected from weight loss, leukocytosis,neutrophilia and diarrhoea. These PDE4 inhibitor-mediated side effectsrelate particularly to the occurrence of diarrhoea.

The present invention further relates to the use of an NSAID (a) forreducing the side effects of one or more PDE4-inhibitors in thetreatment of a disease selected from among respiratory complaints,pulmonary diseases, gastrointestinal ailments and diseases and alsoinflammatory diseases of the joints, skin or eyes, cancers and diseasesof the peripheral or central nervous system.

In another aspect the present invention relates to the use of acombination containing one or more PDE4-inhibitors and at least oneNSAID (a) for the treatment of a disease selected from among respiratorycomplaints, pulmonary diseases, gastrointestinal ailments and diseasesand also inflammatory diseases of the joints, skin or eyes, cancers anddiseases of the peripheral or central nervous system.

It is also preferable to use a combination of one or more, preferablyone, PDE4 inhibitor of general formula 1,

wherein X, R¹, R², and R³ are defined as hereinbefore and according tothe preferred definitions, and at least one NSAID for preparing a drugcombination for the treatment of one of the diseases selected fromrespiratory complaints, pulmonary diseases, gastrointestinal ailmentsand diseases and also inflammatory diseases of the joints, skin or eyes,cancers and diseases of the peripheral or central nervous system, butparticularly for the treatment of inflammatory and obstructive diseasessuch as COPD, chronic sinusitis, asthma, Crohn's disease, and ulcerativecolitis.

In a preferred aspect the invention relates to the use of thecombination containing one or more PDE4-inhibitors—particularly one ormore of the PDE4-inhibitors according to formula 1—and of the at leastone NSAID (2) for preparing a drug combination for the treatment of theabove mentioned diseases, characterised in that the PDE4inhibitor—particularly the PDE4 inhibitor of formula 1—and the at leastone NSAID (2) are administered together and simultaneously in a singleformulation, this single formulation preferably being an oralformulation such as for example a tablet, capsule or the like.

It is also preferable to use the combination containing one or morePDE4-inhibitors—particularly one or more of the PDE4-inhibitorsaccording to formula 1—and the at least one NSAID (2) to prepare a drugcombination for the treatment of the above mentioned diseases,characterised in that the PDE4 inhibitor—particularly the PDE4 inhibitorof formula 1—and the at least one NSAID (2) are administered in twoseparate formulations separated from one another within a time intervalof 0 to 6 hours. In this separate administration in two separateformulations the formulation containing the PDE4 inhibitor—particularlythe PDE4 inhibitor of formula 1—may be an oral or inhalativeformulation, but is preferably an oral formulation, and the formulationcontaining the at least one NSAID (2) is preferably an oral formulation.Moreover, when the combination is used in separate formulations toprepare a drug combination for the treatment of the above mentioneddiseases the formulation containing the PDE4 inhibitor—particularly thePDE4 inhibitor of formula 1—is preferably administered once a day andthe formulation containing the at least one NSAID (2) is preferablyadministered either once or twice a day.

It is also preferable to use the combination containing one or morePDE4-inhibitors—particularly one or more of the PDE4-inhibitorsaccording to formula 1—and the at least one NSAID (2) to prepare a drugcombination for the treatment of the above mentioned diseases, usingPDE4-inhibitors of general formula 1, wherein

-   R¹ is H,-   R² is a group selected from among

-   R³ is a group selected from among

In particular, in the uses mentioned above, the PDE4-inhibitors offormula 1 are selected from:

-   1.1    (3-fluorophenyl)-[5-oxo-2-(4-thiazol-2-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-amine-   1.2    (R)-3-methyl-2-[5-oxo-2-(4-thiazol-2-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-butan-1-ol-   1.3    [2-(4-benzoxazol-2-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5λ□⁴-thieno[3,2-d]pyrimidin-4-yl]-(3-fluorophenyl)-amine-   1.4    [2-(4-benzoxazol-2-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-(tetrahydropyran-4-yl)-amine-   1.5    (R)-2-{2-[4-(6-chloropyridazin-3-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-3-methylbutan-1-ol-   1.6    {2-[4-(6-chloropyridazin-3-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-(3-fluorophenyl)-amine-   1.7    (R)-2-[2-(4-benzoxazol-2-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-3-methylbutan-1-ol-   1.8    (1-{2-[4-(5-chloropyridin-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-cyclopropyl)-methanol-   1.9    {2-[4-(5-chloropyridin-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-(tetrahydropyran-4-yl)-amine-   1.10    {2-[4-(3-dimethylaminopyridazin-4-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-(3-fluorophenyl)-amine-   1.11    6-chloro-4-{4-[4-(3-fluorophenylamino)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-2-yl]-piperazin-1-yl}-pyridazin-3-ol-   1.12    2-{4-[6-(2-ethoxyethoxy)-pyridazin-3-yl]-piperazin-1-yl}-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl)-(3-fluorophenyl)-amine-   1.13    (3-fluorophenyl)-[5-oxo-2-(4-pyridazin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-amine-   1.14    (R)-2-{2-[4-(4-methoxy-1-methyl-1H-benzimidazol-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-3-methylbutan-1-ol-   1.15    (R)-2-{2-[4-(7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepin-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-3-methylbutan-1-ol-   1.16    (R)-3-methyl-2-[5-oxo-2-(4-pyrimidin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-butan-1-ol-   1.17    4-{4-[4-((R)-1-hydroxymethyl-2-methylpropylamino)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-2-yl]-piperazin-1-yl}-pyridin-2-ol-   1.18    (R)-3-methyl-2-[5-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-butan-1-ol-   1.19    (R)-2-{2-[4-(3-dimethylaminopyridazin-4-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-3-methylbutan-1-ol-   1.20    6-chloro-4-{4-[4-((R)-1-hydroxymethyl-2-methylpropylamino)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-2-yl]-piperazin-1-yl}-pyridazin-3-ol-   1.21    (R)-2-(2-{4-[6-(2-ethoxyethoxy)-pyridazin-3-yl]-piperazin-1-yl}-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino)-3-methylbutan-1-ol-   1.22    (R)-3-methyl-2-[5-oxo-2-(4-pyridazin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-butan-1-ol-   1.23    {1-[5-oxo-2-(4-pyrimidin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-cyclopropyl}-methanol-   1.24    {1-[5-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-cyclopropyl}-methanol-   1.25    (S)-1-methyl-5-[5-oxo-2-(4-pyrimidin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-ylamino]-piperidin-2-one-   1.26    {2-[4-(5-fluoro-1-methyl-1H-benzoimidazol-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl}-(tetrahydropyran-4-yl)-amine-   1.27    [5-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl]-(tetrahydropyran-4-yl)-amine-   1.28    (3-fluorophenyl)-{2-[4-(4-methoxy-1-methyl-1H-benzimidazol-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl}-amine-   1.29    {2-[4-(7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepin-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl}-(3-fluorophenyl)-amine-   1.30    (3-fluorophenyl)-[5-oxo-2-(4-pyrimidin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl]-amine-   1.31    4-{4-[4-(3-fluorophenylamino)-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-2-yl]-piperazin-1-yl}-pyridin-2-ol-   1.32    (3-fluorophenyl)-[5-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl]-amine-   1.33    (3-fluorophenyl)-(2-{4-[4-(4-fluorophenyl)-thiazol-2-yl]-piperazin-1-yl}-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl)-amine-   1.34    [2-(4-benzo[d]isoxazol-3-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl]-(3-fluorophenyl)-amine-   1.35    (R)-2-(2-{4-[4-(4-fluorophenyl)-thiazol-2-yl]-piperazin-1-yl}-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-ylamino)-3-methylbutan-1-ol-   1.36    (R)-2-[2-(4-benzo[d]isoxazol-3-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-ylamino]-3-methylbutan-1-ol.

In these above mentioned uses the NSAIDs (a) are preferably selectedfrom among: aceclofenac (2.1), acemetacin (2.2), acetylsalicylic acid(2.3), alclofenac (2.4), alminoprofen (2.5), amfenac (2.6), ampiroxicam(2.7), antolmetinguacil (2.8), anirolac (2.9), antrafenine (2.10),azapropazone (2.11), benorilate (2.12), bermoprofen (2.13), bindarit(2.14), bromfenac (2.15), bucloxinic acid (2.16), bucolom (2.17),bufexamac (2.18), bumadizone (2.19), butibufen (2.20), butixirate(2.21), carbasalate calcium (2.22), carprofen (2.23), choline magnesiumtrisalicylate (2.24), celecoxib (2.25), cinmetacin (2.26), cinnoxicam(2.27), clidanac (2.28), clobuzarit (2.29), deboxamet (2.30),dexibuprofen (2.31), dexketoprofen (2.32), diclofenac (2.33), diflunisal(2.34), droxicam (2.35), eltenac (2.36), enfenamic acid (2.37),etersalate (2.38), etodolac (2.39), etofenamat (2.40), etoricoxib(2.41), feclobuzon (2.42), felbinac (2.43), fenbufen (2.44), fenclofenac(2.45), fenoprofen (2.46), fentiazac (2.47), fepradinol (2.48),feprazone (2.49), flobufen (2.50), floctafenin (2.51), flufenamic acid(2.52), flufenisal (2.53), flunoxaprofen (2.54), flurbiprofen (2.55),flurbiprofenaxetil (2.56), furofenac (2.57), furprofen (2.58),glucametacin (2.59), ibufenac (2.60), ibuprofen (2.61), indobufen(2.62), indometacin (2.63), indometacinfarnesil (2.64), indoprofen(2.65), isoxepac (2.66), isoxicam (2.67), ketoprofen (2.68), ketorolac(2.69), lobenzarit (2.70), lonazolac (2.71), lornoxicam (2.72),loxoprofen (2.73), lumiracoxib (2.74), meclofenamic acid (2.75),meclofen, mefenamic acid (2.76), meloxicam (2.77), mesalazin (2.78),miroprofen (2.79), mofezolac (2.80), nabumetone (2.81), naproxen (2.82),nifluminic acid (2.83), olsalazine (2.84), oxaprozin (2.85), oxipinac(2.86), oxyphenbutazone (2.87), parecoxib (2.88), phenylbutazone (2.89),pelubiprofen (2.90), pimeprofen (2.91), pirazolac (2.92), priroxicam(2.93), pirprofen (2.94), pranoprofen (2.95), prifelon (2.96), prinomod(2.97), proglumetacin (2.98), proquazone (2.99), protizinic acid(2.100), rofecoxib (2.101), romazarit (2.102), salicylamide (2.103),salicylic acid (2.104), salmistein (2.105), salnacedin (2.106),salsalate (2.107), sulindac (2.108), sudoxicam (2.109), suprofen(2.110), talniflumat (2.111), tenidap (2.112), tenosal (2.113),tenoxicam (2.114), tepoxalin (2.115), tiaprofenic acid (2.116), taramide(2.117), tilnoprofenarbamel (2.118), timegadine (2.119), tinoridine(2.120), tiopinac (2.121), tolfenamic acid (2.122), tolmetin (2.123),ufenamate (2.124), valdecoxib (2.125), ximoprofen (2.126), zaltoprofen(2.127) and zoliprofen (2.128).

More preferably, in the uses mentioned above, the NSAIDs (2) areselected from among acetylsalicylic acid (2.3), celecoxib (2.25),diclofenac (2.33), ibuprofen (2.61), indometacin (2.63), lumiracoxib(2.74), meloxicam (2.77), naproxen (2.82) and priroxicam (2.93).

Particularly, in the uses mentioned above, the NSAIDs (a) are selectedfrom among

-   -   acetylsalicylic acid (2.3), preferably in a single dose of 50 to        2000 mg, more preferably 100 to 500 mg,    -   diclofenac (2.33), preferably in a single dose of 25 to 150 mg,        more preferably 25 to 100 mg,    -   meloxicam (2.77), preferably in a single dose of 7.5 to 30 mg,        more preferably 10 to 20 mg    -   naproxen (2.82), preferably in a single dose of 250 to 1000 mg,        more preferably 250 to 750 mg, and    -   ibuprofen (2.61), preferably in a single dose of 200 to 2400 mg,        more preferably 200 to 800 mg used,        while this single dose may be administered once or twice a day.

Preferably, in the above-mentioned uses of the combination for treatingthe above mentioned diseases the PDE4 inhibitor of general formula 1 isgiven in a single dose of 0.01 mg to 50 mg, preferably 0.05 to 30 mg,more preferably 0.1 to 20 mg, particularly 0.5 to 10 mg.

In particular, the invention relates to the above mentioned uses,wherein the or at least one or more of the PDE4 inhibitor-mediated sideeffects is substantially reduced or prevented completely, by comparisonwith the sole administration of the PDE4 inhibitor used in the drugcombination.

The invention also particularly relates to the use of NSAIDs, preferablyas hereinbefore defined and according to the preferred definitions, forreducing or avoiding one or more PDE4 inhibitor-mediated side effects.

These PDE4 inhibitor-mediated side effects are preferably selected fromamong weight loss, leukocytosis, neutrophilia, nausea, vomiting,diarrhoea (including the occurrence of inflammatory parameters and theproliferation of fibroblasts in the mesentery). These PDE4inhibitor-mediated side effects are more preferably selected from weightloss, leukocytosis, neutrophilia and diarrhoea. These PDE4inhibitor-mediated side effects relate particularly to the occurrence ofdiarrhoea.

Synthesis Instructions

The compounds of general formula (I) may be prepared according to thefollowing general synthesis scheme in which the substituents of generalformula (I) have the meanings given hereinbefore. These methods are tobe understood as illustrating the invention without restricting it totheir subject-matter.

1. Synthesis of(3-fluorophenyl)-[5-oxo-2-(4-thiazol-2-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-amine(Example 1.1) 1.1(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(3-fluorophenyl)-amine(III-1)

4 g (II) are placed in 15 ml dimethylformamide, then 4.5 mldiisopropylethylamine are added followed by 2.5 ml 3-fluorophenylamine.The reaction mixture is heated to 120° C. until there is no furtherreaction then cooled and evaporated down. The residue is mixed withwater. The product is extracted with dichloromethane and purified bychromatography (silica gel, petroleum ether/ethyl acetate 80/20 to60/40). 2.6 g (III-1) are obtained in the form of a solid. AnalyticalHPLC (method A): RT=3.27 min.

1.22-chloro-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl)-(3-fluorophenyl)-amine(IV-1)

0.102 g S-(−)-1,1′-bi-2-naphthol are placed in 0.5 ml chloroform underargon, then 0.052 ml titanium(IV)-isopropoxide and 0.064 ml of water areadded. The reaction mixture is stirred for 45 minutes at ambienttemperature. Then a suspension of 0.5 g (III-1) in 25 ml chloroform isadded. The reaction mixture is cooled to −2°/−4° C. and after 20 minutes0.323 ml tert-butylhydroperoxide 5-6 M in decane are added dropwise. Thereaction mixture is stirred further at −2/−4° C. until there is nofurther reaction, and mixed with water. The product is extracted withdichloromethane and purified by chromatography (silica gel,dichloromethane/methanol 100/0 to 95/5). 0.47 g (IV-1) are obtained inthe form of a solid. Analytical HPLC-MS (method A): RT=1.16 min.

1.3(3-fluorophenyl)-[5-oxo-2-(4-thiazol-2-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-amine(Example 1.1)

0.2 g (IV-1) is placed in 3 ml dioxane, 240 μl diisopropylethylamine and0.24 g 1-thiazol-2-yl-piperazin are added. The reaction mixture isheated to 120° C. in the microwave until there is no further reactionand mixed with water. The precipitated solid is suction filtered andpurified by chromatography (silica gel, ethyl acetate/methanol 100/0 to80/20). 0.17 g Example 1.1 are obtained in the form of a solid.Analytical HPLC-MS (method A): RT=1.07 min.

2. Synthesis of(R)-3-methyl-2-[5-oxo-2-(4-thiazol-2-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-butan-1-ol(Example 1.2) 2.1(R)-2-(2-chloro-6,7-dihydro-thieno[3,2-d]pyrimidin-4-ylamino)-3-methyl-butan-1-ol(III-2)

7.2 g 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine (II) are placedin 36 ml dioxane, then 18 ml diisopropylethylamine are added followed by6.1 g (R)-(−)-2-amino-3-methyl-1-butanol. The reaction mixture is heatedto 100° C. until there is no further reaction, then cooled andevaporated down. The residue is treated with petroleum ether/ethylacetate 9:1 in the ultrasound bath and the solid is suction filtered anddried. 8.3 g (III-2) are obtained in the form of a solid. AnalyticalHPLC (method A): RT=2.75 min

2.2(R)-2-(2-chloro-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino)-3-methyl-butan-1-ol(IV-2)

4.1 g S-(−)-1,1′-bi-2-naphthol are placed in 15 ml chloroform underargon, then 0.44 ml titanium(IV)-isopropoxide and 0.54 ml of water areadded. The reaction mixture is stirred for 1 hour at ambienttemperature. Then a suspension of 4.1 g (III-2) in 107 mldichloromethane is added. The reaction mixture is cooled to −2° C. andafter 30 minutes 2.7 ml tert-butylhydroperoxide 5-6 M in decane areadded dropwise. The reaction mixture is stirred further at −2° C. untilthere is no further reaction and made basic with NH₄OH. The product isextracted with dichloromethane and purified by chromatography (silicagel, ethyl acetate/methanol 100/0 to 86/14). 2.45 g (IV-2) are obtainedin the form of a solid. Analytical HPLC-MS (method A): RT=0.98 min

2.3(R)-3-methyl-2-[5-oxo-2-(4-thiazol-2-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-butan-1-ol(Example 1.2)

Starting from 0.2 g (IV-2) and 0.245 g 1-thiazol-2-yl-piperazine, 0.13 gExample 1.2 are prepared analogously to Example 1.1 (cf. 1.3). Thereaction mixture is mixed with water and the product is extracted withdichloromethane and purified by chromatography (silica gel,dichloromethane/methanol 100/0 to 90/10). Analytical HPLC-MS (method A):RT=0.87 min.

3. Synthesis of[2-(4-benzoxazol-2-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5λ□⁴-thieno[3,2-d]pyrimidin-4-yl]-(3-fluorophenyl)-amine(Example 1.3)

Starting from 0.2 g (IV-1) (cf. 1.2) and 0.287 g2-piperazin-1-yl-benzoxazole 0.31 g Example 1.3 are prepared analogouslyto Example 1.1 (cf. 1.3). The reaction mixture is mixed with water andthe product is suction filtered. Analytical HPLC-MS (method A): RT=1.23min.

4. Synthesis of[2-(4-benzoxazol-2-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-(tetrahydropyran-4-yl)-amine(Example 1.4) 4.1(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(tetrahydropyran-4-yl)-amine(III-3)

0.68 g (II) are placed in 6 ml dioxane, then 1.72 mldiisopropylethylamine are added followed by 0.6 g4-aminotetrahydropyran. The reaction mixture is heated to 130° C. untilthere is no further reaction, then cooled and evaporated down. Theproduct is treated with water in the ultrasound bath and the solid issuction filtered and dried. 0.66 g (III-3) are obtained. AnalyticalHPLC-MS (method A): RT=1.08 min.

4.2(2-chloro-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl)-(tetrahydropyran-4-yl)-amine(IV-3)

0.14 g S-(−)-1,1′-bi-2-naphthol are placed in 5 ml chloroform underargon, then 0.072 ml titanium(IV)-isopropoxide and 0.087 ml of water areadded. The reaction mixture is stirred for 45 minutes at ambienttemperature. Then a suspension of 0.66 g (III-3) in 25 ml chloroform isadded. The reaction mixture is cooled to −10° C. and after 60 minutes0.444 ml tert-butylhydroperoxide 5-6 M in decane are added dropwise. Thereaction mixture is stirred further at −10 to −4° C. until there is nofurther reaction and mixed with water. The product is extracted withdichloromethane and purified by chromatography (silica gel, ethylacetate/methanol 100/0 to 80/20). 0.42 g (IV-3) are obtained in the formof a solid. Analytical HPLC-MS (method A): RT=0.94 min.

4.3[2-(4-benzoxazol-2-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-(tetrahydropyran-4-yl)-amine(Example 1.4)

Starting from 0.2 g (IV-3) and 0.315 g 2-piperazin-1-yl-benzoxazole, 0.3g Example 1.4 are prepared and worked up analogously to Example 1.3 (cf.3.). Analytical HPLC-MS (method A): RT=1.04 min.

5. Synthesis of(R)-2-{2-[4-(6-chloropyridazin-3-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-3-methylbutan-1-ol(Example 1.5)

Starting from 0.2 g (IV-2) (cf. 2.2) and 0.287 g3-chloro-6-piperazin-1-yl-pyridazine, 0.257 g Example 1.5 are preparedand worked up analogously to Example 1.3 (cf. 3.). Analytical HPLC-MS(method A): RT=0.98 min.

6. Synthesis of{2-[4-(6-chloropyridazin-3-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-(3-fluorophenyl)-amine(Example 1.6)

Starting from 0.2 g (IV-1) (cf. 1.2) and 0.28 g3-chloro-6-piperazin-1-yl-pyridazine, 0.31 g Example 1.6 are preparedanalogously to Example 1.3 (cf. 3.). Analytical HPLC-MS (method A):RT=1.12 min.

7. Synthesis of(R)-2-[2-(4-benzoxazol-2-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-3-methylbutan-1-ol(Example 1.7)

Starting from 0.2 g (IV-2) (cf. 2.2) and 0.313 g2-piperazin-1-yl-benzoxazole, 0.16 g Example 1.7 are preparedanalogously to Example 1.1 (cf. 1.3). The reaction mixture is mixed withwater and the product is extracted with dichloromethane and purified bychromatography (silica gel, ethyl acetate/methanol 100/0 to 80/20).Analytical HPLC-MS (method A): RT=1.06 min.

8. Synthesis of(1-{2-[4-(5-chloropyridin-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-cyclopropyl)-methanol(Example 1.8) 8.1 tert-butyl (1-hydroxymethylcyclopropyl)-carbamidate

1 g 1-(BOC-amino)-cyclopropanecarboxylic acid is dissolved in 20 mldimethoxyethane and cooled to −70° C. Then 0.65 ml N-methylmorpholineare added and 0.71 ml isobutylchloroformate in 5 ml dimethoxyethane areadded dropwise. The reaction mixture is heated to −5° C. The precipitateis suction filtered. The eluate is cooled to −15° C. and 0.303 g sodiumborohydride are slowly added. The reaction mixture is then stirred for30 minutes at ambient temperature, mixed with water and the product isextracted with dichloromethane. The organic phase is dried andevaporated to dryness. 1.04 g product are obtained in the form of asolid. ¹H NMR (400 MHz, DMSO): 1.36 (9H, s); 0.61 (2H, t); 0.52 (2H, t).

8.2 1-aminocyclopropanemethanol

1.04 g tert-butyl(1-hydroxymethylcyclopropyl)-carbamidate are placed in5 ml dioxane. 2.5 ml HCl in dioxane (4 mol/l) are added dropwise. Thereaction mixture is stirred for 15 h at ambient temperature. The solventis evaporated down by half and the precipitated solid is suctionfiltered. 0.5 g product are obtained as the hydrochloride. ¹H NMR (400MHz, DMSO): 5.27 (1H, t); 0.91 (2H, t); 0.71 (2H, t).

8.3[1-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-cyclopropyl]-methanol(III-4)

1.4 g (II) are placed in 10 ml dioxane, then first 3.6 mldiisopropylethylamine are added followed by 1 g1-aminocyclopropanemethanol (cf. 8.2). The reaction mixture is heated to160° C. until there is no further reaction, then cooled and evaporateddown. The residue is treated with cyclohexane/ethyl acetate (8:2) in theultrasound bath and the solid is suction filtered and dried. 1.24 g(III-4) are obtained in the form of a solid. Analytical HPLC-MS (methodA): RT=1.01 min.

8.4[1-(2-chloro-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino)-cyclopropyl]-methanol(IV-4)

0.28 g S-(−)-1,1′-bi-2-naphthol are placed in 20 ml chloroform underargon, then 0.14 ml titanium(IV)-isopropoxide and 0.17 ml of water areadded. The reaction mixture is stirred for 1 hour at ambienttemperature. Then a suspension of 1.2 g (III-4) in 40 ml dichloromethaneand 2 ml of methanol is added. The reaction mixture is cooled to −5° C.and after 30 minutes 0.91 ml of tert-butylhydroperoxide 5-6 M in decaneare added dropwise. The reaction mixture is stirred further at −5° C.until there is no further reaction and made basic with NH₄OH. Theaqueous phase is washed with dichloromethane and freeze-dried. 1 g(IV-4) is obtained in the form of a solid. Analytical HPLC-MS (method A)RT=0.85 min.

8.5(1-{2-[4-(5-chloropyridin-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-cyclopropyl)-methanol(Example 1.8)

0.1 g (IV-4) is placed in 3 ml N-methyl-2-pyrrolidone, then 182 μldiisopropylethylamine and 0.08 g 1-(5-chloropyridin-2-yl)-piperazine areadded. The reaction mixture is heated to 120° C. in the microwave untilthere is no further reaction. The product is purified by chromatography(preparative HPLC, method A). Analytical HPLC-MS (method B): RT=1.09min.

9. Synthesis of{2-[4-(5-chloropyridin-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-(tetrahydropyran-4-yl)-amine(Example 1.9)

Starting from 0.11 g (IV-3) (cf. 4.2) and 0.083 g1-(5-chloropyridin-2-yl)-piperazine, 0.14 g Example 1.9 are prepared andpurified analogously to Example 1.8 (cf. 8.5). Analytical HPLC-MS(method B): RT=1.14 min.

10. Synthesis of{2-[4-(3-dimethylaminopyridazin-4-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-(3-fluorophenyl)-amine(Example 1.10) 10.1 3,4,6-trichloropyridazine

44 g 3,6-dichloropyridazine and 22 g aluminium trichloride are heated to140° C. At this temperature 10.6 l chlorine are piped into the reactionmixture over a period of 4 hours. After cooling the product is extractedwith toluene, washed with a 10% sodium chloride solution and distilled(bp=127-129° C.). 44.1 g of product are obtained.

10.2 3,6-dichloro-4-piperazin-1-yl-pyridazine

18 g 3,4,6-trichloro-pyridazine and 34 g piperazine are suspended in 100ml of ethanol and stirred for 30 minutes at ambient temperature. Theprecipitated solid is suction filtered. 500 ml of water are added to themother liquor and the precipitated product is suction filtered. 14 gproduct are obtained in the form of a solid. M.p.=111-115° C.

10.3 (6-chloro-4-piperazin-1-yl-pyridazin-3-yl)-dimethylamine

23 g 3,6-dichloro-4-piperazin-1-yl-pyridazine and 45 g dimethylamine aresuspended in 200 ml of methanol and autoclaved for 4 hours at 100° C.The reaction mixture is evaporated to dryness and the product isextracted with chloroform and washed with sodium hydroxide solution. Thehydrochloride is precipitated with an ethereal HCl solution. 27 gproduct are obtained. M.p.=291° C.

10.4 dimethyl-(4-piperazin-1-yl-pyridazin-3-yl)-amine (V-1)

9.4 g (6-chloro-4-piperazin-1-yl-pyridazin-3-yl)-dimethylaminehydrochloride and 7.3 g sodium acetate are suspended in 150 ml ofmethanol and hydrogenated with 1 g Pd/C 10% at ambient temperature. Thecatalyst is suction filtered, the filtrate is evaporated to dryness andthe product is extracted with chloroform and washed with sodiumhydroxide solution. The hydrochloride is precipitated with an etherealHCl solution. 7 g (V-1) are obtained. M.p.=335° C.

10.5{2-[4-(3-dimethylaminopyridazin-4-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-(3-fluorophenyl)-amine(Example 1.10)

(IV-1) (cf. 1.2) (0.1 mmol) is placed in 750 μl N-methyl-2-pyrrolidone(NMP) and 50 μl diisopropylethylamine, mixed with a solution of (V-1)(0.1 mmol) in 400 μl NMP and heated to 120° C. in the microwave for 30min. Then 600 μL DMF are added, the reaction solution is purified bychromatography (preparative HPLC-MS, method A) and the product fractionsare freeze-dried. Example 1.10 is obtained as the trifluoroacetate.Analytical HPLC-MS (method C): RT=1.61 min.

11. Synthesis of6-chloro-4-{4-[4-(3-fluorophenylamino)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-2-yl]-piperazin-1-yl}-pyridazin-3-ol(Example 1.11) 11.1(6-chloro-4-piperazin-1-yl-pyridazin-3-yloxy)-ethanol

23 g 3,6-dichloro-4-piperazin-1-yl-pyridazine (cf. 10.2) are suspendedin 100 ml ethyleneglycol and added dropwise to a suspension of 2.3 gsodium in 100 ml ethyleneglycol. The reaction mixture is heated to 100°C. for 3 hours and evaporated to dryness. The residue is suspended inacetonitrile and the solid is suction filtered. The mother liquor isevaporated to dryness, the product is extracted with dichloromethane andwashed with conc. NaOH. The product is suspended in ethanol andprecipitated as the fumarate with fumaric acid. 13 g product areobtained. M.p.=179° C.

11.2 6-chloro-4-piperazin-1-yl-pyridazin-3-ol (V-2)

15 g (6-chloro-4-piperazin-1-yl-pyridazin-3-yloxy)-ethanol fumarate aresuspended in 90 ml hydrogen bromide (48%). The reaction mixture isstirred for 1 hour at reflux temperature and evaporated to dryness. 19 gproduct are obtained as the hydrobromide. M.p.=35° C.

11.36-chloro-4-{4-[4-(3-fluorophenylamino)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-2-yl]-piperazin-1-yl}-pyridazin-3-ol(Example 1.11)

Starting from (IV-1) (cf. 1.2) and (V-2) Example 1.11 is prepared andpurified analogously to Example 1.10 (cf. 10.5). Analytical HPLC-MS(method C): RT=1.86 min.

12. Synthesis of(2-{4-[6-(2-ethoxyethoxy)-pyridazin-3-yl]-piperazin-1-yl}-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl)-(3-fluorophenyl)-amine(Example 1.12) 12.1 3-ethoxyethoxy-6-piperazin-1-yl-pyridazine (V-3)

18 g 3-chloro-6-piperazin-1-yl-pyridazine and 30 g potassium hydroxidein 30 ml of water are suspended in 180 ml ethylglycol and stirred for 4hours at reflux temperature. The reaction mixture is evaporated todryness. The product is extracted with diethyl ether, washed with aconcentrated potassium carbonate solution and distilled (bp=190° C.). 18g (V-3) are obtained.

12.2(2-{4-[6-(2-ethoxyethoxy)-pyridazin-3-yl]-piperazin-1-yl}-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl)-(3-fluorophenyl)-amine(Example 1.12)

Starting from (IV-1) (cf. 1.2) and (V-3) Example 1.12 is prepared andpurified as the trifluoroacetate analogously to Example 1.10 (cf. 10.5).Analytical HPLC-MS (method C): RT=1.66 min.

13. Synthesis of(3-fluorophenyl)-[5-oxo-2-(4-pyridazin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-amine(Example 1.13) 13.1 4-piperazin-1-yl-pyridazine (V-4)

9.3 g 3,6-dichloro-4-piperazin-1-yl-pyridazine (cf. 10.2) and 6.5 gsodium acetate are suspended in 100 ml of methanol and hydrogenated with1 g Pd/C 10% at ambient temperature. The catalyst is suction filteredand the filtrate is evaporated to dryness. The product is extracted withchloroform, washed with sodium hydroxide solution and precipitated asthe hydrochloride with an ethereal HCl solution. 8.6 g (V-4) areobtained. M.p.>300° C.

13.2(3-fluorophenyl)-[5-oxo-2-(4-pyridazin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-amine(Example 1.13)

Starting from (IV-1) (cf. 1.2) and (V-4) Example 1.13 is prepared andpurified as the trifluoroacetate analogously to Example 1.10 (cf. 10.5).Analytical HPLC-MS (method C): RT=1.54 min.

14. Synthesis of(R)-2-{2-[4-(4-methoxy-1-methyl-1H-benzimidazol-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-3-methylbutan-1-oltrifluoroacetate (Example 1.14) 14.1tert-butyl(3-methoxy-2-nitrophenyl)-carbamidate

10 g 3-methoxy-2-nitrobenzoic acid and 7 ml triethylamine are placed in100 ml tent-butanol and 11 ml diphenylphosphorylazide are addeddropwise. The reaction mixture is then stirred for 6 hours at refluxtemperature and evaporated to dryness. The product is extracted withethyl acetate, then washed with a 10% citric acid, a saturated sodiumhydrogen carbonate and a saturated sodium chloride solution. 12.4 gproduct are obtained as a solid. M.p.=90° C.

14.2 tert-butyl(3-methoxy-2-nitrophenyl)-methyl-carbamidate

12.2 g tert-butyl(3-methoxy-2-nitrophenyl)-methyl-carbamidate are placedin 80 ml dimethylformamide and cooled at 0° C. 2.4 g sodium hydride (50%in mineral oil) are slowly added. The reaction mixture is stirred for 30minutes at 0° C. Then 3.1 ml methyl iodide are added dropwise. Thereaction mixture is stirred for 2 hours at ambient temperature and mixedwith water. The product is extracted with ethyl acetate. 12.5 g productare obtained as an oil.

14.3 (3-methoxy-2-nitrophenyl)-methylamine

12.5 g tert-butyl(3-methoxy-2-nitrophenyl)-methyl-carbamidate and 78 mlhydrochloric acid (4 M) are suspended in 300 ml of ethyl acetate andheated for 5 hours at 60° C. The reaction mixture is evaporated todryness, the residue is combined with a saturated sodium hydrogencarbonate solution and the product is extracted with ethyl acetate. 7.5g product are obtained in the form of a solid. M.p=58-59° C.

14.4 3-methoxy-N¹-methylbenzene-1,2-diamine

7.4 g (3-methoxy-2-nitrophenyl)-methylamine are suspended in 150 ml ofethyl acetate and hydrogenated with 1 g Pd/C 10% at a pressure of 50 psiand at ambient temperature. After 4.5 hours the catalyst is suctionfiltered and the filtrate is evaporated to dryness. 5.9 g of the productare obtained as an oil.

14.5 4-methoxy-1-methyl-1,3-dihydrobenzimidazol-2-one

5.9 g 3-methoxy-N1-methylbenzol-1,2-diamine are suspended in 70 ml oftetrahydrofuran and 6.3 g N,N′-carbonyldiimidazole are added. Thereaction mixture is stirred for 5 hours at ambient temperature, mixedwith water and the product is extracted with ethyl acetate. 3.9 gproduct are obtained as a solid.

14.6 2-chloro-4-methoxy-1-methyl-1H-benzimidazole

3.7 g 4-methoxy-1-methyl-1,3-dihydrobenzimidazol-2-one are suspended in15 ml phosphorus oxychloride. The reaction mixture is stirred for 3hours at reflux temperature, ice water is slowly added and the mixtureis made alkaline with conc. ammonia. The precipitated product is suctionfiltered. 3.6 g product are obtained in the form of a solid.M.p.=118-119° C.

14.7 4-methoxy-1-methyl-2-piperazin-1-yl-1-benzimidazole (V-5)

2 g 2-chloro-4-methoxy-1-methyl-1H-benzimidazole and 4.4 g piperazineare suspended in 20 ml n-butanol and stirred for 5 hours at refluxtemperature. The reaction mixture is evaporated to dryness and theproduct is purified by chromatography (silica gel,dichloromethane/methanol 10:1). 1.6 g (V-5) are obtained in the form ofa solid. M.p.=147° C.

14.8(R)-2-{2-[4-(4-methoxy-1-methyl-1H-benzimidazol-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-3-methylbutan-1-ol(Example 1.14)

Starting from (IV-2) (cf. 2.2) and (V-5), Example 1.14 is prepared andpurified as the trifluoroacetate analogously to Example 1.10 (cf. 10.5).Analytical HPLC-MS (method C): RT=1.5 min.

15. Synthesis of(R)-2-{2-[4-(7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepin-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-3-methylbutan-1-ol(Example 1.15) 15.12-chloro-7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine

26.5 g of 7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepin-2-ylamine(U.S. Pat. No. 4,409,220) are suspended in 130 ml conc. hydrochloricacid, combined with 0.1 g copper(I)bromide and cooled to −5° C. Asuspension of 11 g sodium nitrite in 14 ml of water is slowly addeddropwise. The reaction mixture is stirred for 15 hours at ambienttemperature and evaporated almost to dryness. The residue is slowlyadded to ice water and potassium carbonate. The product is extractedwith dichloromethane and precipitated as the hydrochloride with anethereal HCl solution. 14.3 g product are obtained. M.p.=258-262° C.

15.27-ethyl-2-piperazin-1-yl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine(V-6)

3 g 2-chloro-7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine arecombined with 23.3 g piperazine and the mixture is heated to 145° C. for5 hours. Excess piperazine is distilled off and the residue is treatedwith dichloromethane and methanol. Any product precipitated is suctionfiltered and purified by chromatography (Alox,dioxane/toluene/methanol/NH₄OH 50/20/20/2). 1.95 g product are obtained.

15.3(R)-2-{2-[4-(7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepin-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-3-methylbutan-1-ol(Example 1.15)

Starting from (IV-2) (cf. 2.2) and (V-6) Example 1.15 is prepared andpurified as the trifluoroacetate analogously to Example 1.10 (cf. 10.5).Analytical HPLC-MS (method C): RT=1.38 min.

16. Synthesis of(R)-3-methyl-2-[5-oxo-2-(4-pyrimidin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-butan-1-ol(Example 1.16)

Starting from (IV-2) (cf. 2.2) and 4-piperazin-1-yl-pyrimidine (J. Org.Chem. 1953, 1484) Example 1.16 is prepared and purified as thetrifluoroacetate analogously to Example 1.10 (cf. 10.5). AnalyticalHPLC-MS (method C): RT=1.31 min.

17. Synthesis of4-{4-[4-((R)-1-hydroxymethyl-2-methylpropylamino)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-2-yl]-piperazin-1-yl}-pyridin-2-ol(Example 1.17) 17.1 4-(1-oxypyridin-4-yl)-piperazin-1-BOC

3 g 4-chloropyridine-N-oxide and 13.2 g piperazine-1-BOC are heated to90° C. for 4 hours. The product is purified by chromatography (silicagel, dichloromethane/methanol/ammonia 90/10/1). 2.9 g product areobtained in the form of a solid.

17.2 4-(2-hydroxypyridin-4-yl)-piperazine-1-BOC

1.75 g 4-(1-oxypyridin-4-yl)-piperazin-1-BOC are suspended in 15 mlacetic anhydride and heated to 150° C. for 24 h. The reaction mixture isevaporated to dryness and the product is purified by chromatography(silica gel, ethyl acetate/methanol/ammonia 95/5/0.5). 0.51 g productare obtained in the form of a solid

17.3 4-piperazin-1-yl-pyridin-2-ol (V-7)

0.51 g 4-(2-hydroxypyridin-4-yl)-piperazine-1-BOC and 2 mltrifluoroacetic acid are suspended in 15 ml dichloromethane and stirredfor 2 hours at ambient temperature. The reaction mixture is evaporatedto dryness. 1 g (V-7) are obtained as an oil. ¹H NMR (400 MHz, DMSO):7.30 (1H, d); 5.99 (1H, dd); 5.34 (1H, d).

17.44-{4-[4-((R)-1-hydroxymethyl-2-methylpropylamino)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-2-yl]-piperazin-1-yl}-pyridin-2-ol(Example 1.17)

Starting from (IV-2) (cf. 2.2) and (V-7) Example 1.17 is prepared andpurified analogously to Example 1.10 (cf. 10.5). Analytical HPLC-MS(method C): RT=1.37 min.

18. Synthesis of(R)-3-methyl-2-[5-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-butan-1-oltrifluoroacetate (Example 1.18)

Starting from (IV-2) (cf. 2.2) and 1-pyridin-4-yl-piperazine Example1.18 is prepared and purified as the trifluoroacetate analogously toExample 1.10 (cf. 10.5). Analytical HPLC-MS (method C): RT=1.33 min.

19. Synthesis of(R)-2-{2-[4-(3-dimethylaminopyridazin-4-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-3-methylbutan-1-ol(Example 1.19)

Starting from (IV-2) (cf. 2.2) and (V-1) (cf. 10.4) Example 1.19 isprepared and purified as the trifluoroacetate analogously to Example1.10 (cf. 10.5). Analytical HPLC-MS (method C): RT=1.37 min.

20. Synthesis of6-chloro-4-{4-[4-((R)-1-hydroxymethyl-2-methylpropylamino)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-2-yl]-piperazin-1-yl}-pyridazin-3-ol(Example 1.20)

Starting from (IV-2) (cf. 2.2) and (V-2) (cf. 11.2) Example 1.20 isprepared and purified analogously to Example 1.10 (cf. 10.5). AnalyticalHPLC-MS (method C): RT=1.55 min.

21. Synthesis of(R)-2-(2-{4-[6-(2-ethoxyethoxy)-pyridazin-3-yl]-piperazin-1-yl}-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino)-3-methylbutan-1-ol(Example 1.21)

Starting from (IV-2) (cf. 2.2) and (V-3) (cf. 12.1) Example 1.21 isprepared and purified as the trifluoroacetate analogously to Example1.10 (cf. 10.5). Analytical HPLC-MS (method C): RT=1.45 min.

22. Synthesis of(R)-3-methyl-2-[5-oxo-2-(4-pyridazin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-butan-1-ol(Example 1.22)

Starting from (IV-2) (cf. 2.2) and (V-4) (cf. 13.1) Example 1.22 isprepared and purified as the trifluoroacetate analogously to Example1.10 (cf. 10.5). Analytical HPLC-MS (method C): RT=0.56 min.

23. Synthesis of{1-[5-oxo-2-(4-pyrimidin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-cyclopropyl}-methanoltrifluoroacetate (Example 1.23)

Starting from (IV-4) (cf. 8.4) and 4-piperazin-1-yl-pyrimidine (J. Org.Chem. 1953, 1484) Example 1.23 is prepared and purified as thetrifluoroacetate analogously to Example 1.10 (cf. 10.5). AnalyticalHPLC-MS (method C): RT=1.29 min.

24 Synthesis of{1-[5-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-cyclopropyl}-methanolTrifluoroacetate (Example 1.24)

Starting from (IV-4) (cf. 8.4) and 1-pyridin-4-yl-piperazine Example1.24 is prepared and purified as the trifluoroacetate analogously toExample 1.10 (cf. 10.5). Analytical HPLC-MS (method C): RT=1.29 min.

25. Synthesis of(S)-1-methyl-5-[5-oxo-2-(4-pyrimidin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-piperidin-2-one(Example 1.25) 25.1 (S)-5-dibenzylaminopiperidin-2-one

0.600 g 4-(S)-amino-delta-valerolactam hydrochloride, 0.970 mlbenzylbromide and 1.5 g sodium hydrogen carbonate are suspended in 30 mlof ethanol. The reaction mixture is then stirred for 8 hours at 80° C.and then evaporated to dryness. The residue is suspended in water andthe product is extracted with dichloromethane and purified bychromatography (silica gel, dichloromethane/methanol 100/0 to 95/5).0.500 g of the product are obtained as an oil. Analytical HPLC-MS(method A): RT=1.01 min.

25.2 (S)-5-dibenzylamino-1-methylpiperidin-2-one

0.500 g (S)-5-dibenzylaminopiperidin-2-one are suspended in 15 ml oftetrahydrofuran. While cooling with the ice bath 0.175 gpotassium-tert-butoxide are added. The reaction mixture is then stirredfor 30 minutes at ambient temperature. While cooling with the ice bath0.095 ml methyl iodide are added. The reaction mixture is then stirredfor 48 hours at ambient temperature and then combined with a saturatedNaCl solution. The product is extracted with ethyl acetate. 0.450 g ofthe product are obtained as an oil. Analytical HPLC-MS (method A):RT=1.07 min.

25.3 (S)-5-amino-1-methylpiperidin-2-one

0.450 g (S)-5-dibenzylamino-1-methylpiperidin-2-one are suspended in 25ml of methanol and hydrogenated with 0.150 g Pd/C 10% at a pressure of 3bar and a temperature of 60° C. After 16 hours the catalyst iseliminated by suction filtering and the filtrate is evaporated todryness. 0.190 g of the product are obtained as an oil. ¹H NMR (400 MHz,DMSO): 2.76 (3H, s).

25.4(S)-5-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-1-methylpiperidin-2-one(III-5)

0.27 g (II) are placed in 3 ml dioxane, then 0.45 mldiisopropylethylamine and 0.25 g (S)-5-amino-1-methylpiperidin-2-one areadded. The reaction mixture is heated to 130° C. until there is nofurther reaction, then cooled and evaporated down. The product isextracted with dichloromethane and purified by chromatography(preparative HPLC, method B). 0.26 g (III-5) are obtained in the form ofa solid. Analytical HPLC-MS (method A): RT=1.06 min.

25.5(S)-5-(2-chloro-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino)-1-methylpiperidin-2-one(IV-5)

0.04 g S-(−)-1,1′-bi-2-naphthol are placed in 5 ml chloroform underargon, then 0.02 ml titanium(IV)-isopropoxide and 0.025 ml of water areadded. The reaction mixture is stirred for 1 hour at ambienttemperature. Then a suspension of 0.2 g (III-5) in 4 ml dichloromethaneis added. The reaction mixture is cooled to −5° C. and after 20 minutes0.12 ml tert-butylhydroperoxide 5-6 M in decane are added dropwise. Thereaction mixture is stirred further at −5° C. until there is no furtherreaction and made basic with NH₄OH. The product is extracted withdichloromethane and purified by chromatography (silica gel, ethylacetate/methanol 100/0 to 60/40). 0.09 g (IV-5) are obtained in the formof a solid. Analytical HPLC-MS (method A): RT=0.83 min.

25.6(S)-1-methyl-5-[5-oxo-2-(4-pyrimidin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-piperidin-2-one(Example 1.25)

Starting from (IV-5) and 4-piperazin-1-yl-pyrimidine (J. Org. Chem.1953, 1484) Example 1.25 is prepared and purified as thetrifluoroacetate analogously to Example 1.10 (cf. 10.5). AnalyticalHPLC-MS (method C): RT=1.28 min.

26. Synthesis of{2-[4-(5-fluoro-1-methyl-1H-benzimidazol-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-(tetrahydropyran-4-yl)-amine(Example 1.26) 26.1 (4-fluoro-2-nitrophenyl)-methylamine

7.3 g 1,4-difluoro-2-nitrobenzene are slowly added to a 30 ml 40%aqueous methylamine solution while cooling with ice and the reactionmixture is stirred for 1 hour at ambient temperature. The precipitatedproduct is suction filtered and recrystallised aus water and ethanolumkristallisiert. 6.3 g product are obtained in the form of a solid.M.p.=74-76° C.

26.2 4-fluoro-N¹-methylbenzol-1,2-diamine

6.2 g (4-fluoro-2-nitrophenyl)-methylamine are suspended in 200 ml ofethyl acetate and hydrogenated with 1 g Raney-Nickel at a pressure of 5bar and ambient temperature. After 4.5 hours the catalyst is removed bysuction filtering and the filtrate is evaporated to dryness. 3.9 gproduct are obtained as an oil.

26.3 5-fluoro-1-methyl-1,3-dihydrobenzimidazol-2-one

6 g 4-fluoro-N1-methylbenzol-1,2-diamine are suspended in 200 ml oftetrahydrofuran and 7.1 g N,N′-carbonyldiimidazole are added. Thereaction mixture is stirred for 48 hours at ambient temperature and theprecipitated product is suction filtered and recrystallised fromdioxane. 3.9 g product are obtained in the form of a solid. M.p.=207° C.

26.4 2-chloro-5-fluoro-1-methyl-1H-benzimidazole

3.9 g 5-fluoro-1-methyl-1,3-dihydro-benzimidazol-2-one are suspended in80 ml phosphorus oxychloride and the reaction mixture is stirred for 2hours at reflux temperature. 50 ml diethylaniline are added. Thereaction mixture is stirred for a further 10 minutes at refluxtemperature and ice water is slowly added thereto. The product isextracted with dichloromethane and purified by chromatography (silicagel, cyclohexane, methylene chloride/acetone 20/1). 1.4 g product areobtained in the form of a solid. M.p.=138-141° C.

26.5 5-fluoro-1-methyl-2-piperazin-1-yl-1H-benzimidazole (V-8)

0.7 g 2-chloro-5-fluoro-1-methyl-1H-benzimidazole and 1.3 g piperazineare suspended in 10 ml n-butanol and stirred for 48 hours at ambienttemperature. The reaction mixture is evaporated to dryness and theproduct is purified by chromatography (aluminium oxide, methylenechloride/methanol 10/1). 0.73 g (V-8) are obtained in the form of asolid. ¹H NMR (400 MHz, DMSO): 6.9 (1H, t); 3.6 (3H, s).

26.6{2-[4-(5-fluoro-1-methyl-1H-benzoimidazol-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-(tetrahydropyran-4-yl)-amine(Example 1.26)

Starting from (IV-3) (cf. 4.2) and (V-8) Example 1.26 is prepared andpurified analogously to Example 1.10 (cf. 10.5). Analytical HPLC-MS(method C): RT=1.48 min.

27. Synthesis of[5-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-(tetrahydropyran-4-yl)-amine(Example 1.27)

Starting from (IV-3) (cf. 4.2) and 1-pyridin-4-yl-piperazine Example1.27 is prepared and purified as the trifluoroacetate analogously toExample 15 (cf. 10.5). Analytical HPLC-MS (method C): RT=1.32 min.

28. Synthesis of(3-fluorophenyl)-{2-[4-(4-methoxy-1-methyl-1H-benzimidazol-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-amine(Example 1.28)

Starting from (IV-1) (cf. 1.2) and (V-5) (cf. 14.7) Example 1.28 isprepared and purified as the trifluoroacetate analogously to Example1.10 (cf. 10.5). Analytical HPLC-MS (method C): RT=1.73 min.

29. Synthesis of{2-[4-(7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepin-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-(3-fluorophenyl)-amine(Example 1.29)

Starting from (IV-1) (cf. 1.2) and (V-6) (cf. 15.2) Example 1.29 isprepared and purified as the trifluoroacetate analogously to Example1.10 (cf. 10.5). Analytical HPLC-MS (method C): RT=1.6 min.

30. Synthesis of(3-fluorophenyl)-[5-oxo-2-(4-pyrimidin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-amine(Example 1.30)

Starting from (IV-1) (cf. 1.2) and 4-piperazin-1-yl-pyrimidine (J. Org.Chem. 1953, 1484) Example 1.30 is prepared and purified as thetrifluoroacetate analogously to Example 1.10 (cf. 10.5). AnalyticalHPLC-MS (method C): RT=1.56 min.

31. Synthesis of4-{4-[4-(3-fluorophenylamino)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-2-yl]-piperazin-1-yl}-pyridin-2-ol(Example 1.31)

Starting from (IV-1) (cf. 1.2) and (V-7) (cf. 17.3) Example 1.31 isprepared and purified analogously to Example 1.10 (cf. 10.5). AnalyticalHPLC-MS (method C): RT=1.61 min.

32. Synthesis of(3-fluorophenyl)-[5-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-amine(Example 1.32)

Starting from (IV-1) (cf. 1.2) and 1-pyridin-4-yl-piperazine Example1.32 is prepared and purified analogously to Example 1.10 (cf. 10.5).Analytical HPLC-MS (method C): RT=1.56 min.

33. Synthesis of(3-fluorophenyl)-(2-{4-[4-(4-fluorophenyl)-thiazol-2-yl]-piperazin-1-yl}-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl)-amine(Example 1.33)

Starting from (IV-1) (cf. 1.2) and1-[4-(4-fluorophenyl)-thiazol-2-yl]-piperazine Example 1.33 is preparedand purified analogously to Example 1.10 (cf. 10.5). Analytical HPLC-MS(method C): RT=2.42 min.

34. Synthesis of[2-(4-benzo[d]isoxazol-3-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-(3-fluorophenyl)-amine(Example 1.34)

Starting from (IV-1) (cf. 1.2) and 3-piperazin-1-yl-benzo[d]isoxazoleExample 1.34 is prepared and purified analogously to Example 1.10 (cf.10.5). Analytical HPLC-MS (method C): RT=2.19 min.

35. Synthesis of(R)-2-(2-{4-[4-(4-fluorophenyl)-thiazol-2-yl]-piperazin-1-yl}-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino)-3-methylbutan-1-ol(Example 1.35)

Starting from (IV-2) (cf. 2.2) and1-[4-(4-fluorophenyl)-thiazol-2-yl]-piperazine Example 1.35 is preparedand purified analogously to Example 1.10 (cf. 10.5). Analytical HPLC-MS(method C): RT=1.91 min.

36. Synthesis of(R)-2-[2-(4-benzo[d]isoxazol-3-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-3-methylbutan-1-ol(Example 1.36)

Starting from (IV-2) (cf. 2.2) and 3-piperazin-1-yl-benzo[d]isoxazolExample 1.36 is prepared and purified analogously to Example 1.10 (cf.10.5). Analytical HPLC-MS (method C): RT=1.76 min.

Methods of Chromatography

The Example compounds prepared according to the synthesis schemes shownabove were characterised by the following chromatographic methods,which—if used—are individually specified in Table A.

Analytical HPLC-MS, Method A

Waters ZMD mass spectrometer (positive ionisation (ESI+)), Alliance2690/2695 HPLC (diode array detector, wavelength range: 210 to 500 nm),Waters 2700 Autosampler, Waters 996/2996.

A: water with 0.10% TFA

B: acetonitrile with 0.10% TFA

time in min % A % B flow rate in ml/min 0.00 95 5 2.50 0.20 95 5 2.501.50 2 98 2.50 1.70 2 98 2.50 1.90 95 5 2.50 2.20 95 5 2.50

The stationary phase used is a Merck Chromolith™ Flash RP-18e column,4.6 mm×25 mm (column temperature: constant at 25° C.).

Analytical HPLC-MS, Method B

Waters ZMD mass spectrometer (positive ionisation (ESI+)), Alliance2690/2695 HPLC (diode array detector, wavelength range: 210 to 500 nm),Waters 2700 Autosampler, Waters 996/2996.

A: water with 0.10% NH₃

B: acetonitrile with 0.10% NH₃

time in min % A % B flow rate in ml/min 0.00 95 5 3.00 0.20 95 5 3.001.50 2 98 3.00 1.90 2 98 3.00 2.00 2 98 3.00

The stationary phase used is Waters, X-Bridge, C18, 3.5 nm, 4.6×20 mm,ambient temperature

Analytical HPLC-MS, Method C

Waters ZQ2000 mass spectrometer (positive ionisation (ESI+)), HP1100HPLC (DAD, wavelength range: 210 to 500 nm), and Gilson 215 Autosampler.

A: water with 0.10% TFA

B: acetonitrile with 0.10% TFA

time in min % A % B flow rate in ml/min 0.00 95 5 1.50 2.00 0 100 1.502.50 0 100 1.50 2.60 95 5 1.50

The stationary phase used is a Sunfire C18 column, 4.6×50 mm, 3.5 μm,column temperature 40° C.

Analytical HPLC, Method A

Agilent 1100, diode array detection is carried out in the wavelengthrange 210-380 nm.

A: water with 0.10% TFA

B: acetonitrile with 0.13% TFA

time in min % A % B flow rate in ml/min 0.00 95 5 1.50 0.60 95 5 1.503.40 2 98 1.50 3.90 2 98 1.50 4.20 95 5 1.50 4.90 95 5 1.50

The stationary phase used is a Varian Microsorb column, RP C18, 3 μm,100 A, ambient temperature.

Preparative HPLC-MS, Method A

Waters ZQ2000 mass spectrometer (positive ionisation (ESI+)), HP1100HPLC (DAD, wavelength range: 210-500 nm), and Gilson 215 Autosampler.

A: water with 0.10% TFA

B: acetonitrile

time in min % A % B flow rate in ml/min 0.00 90 10 50 1.50 90 10 50 8.0040 60 50 10.00 40 60 50 11.00 90 10 50

The stationary phase used is a Sunfire C18 column, 30×100 mm, 5 μm,ambient temperature.

Preparative HPLC, Method A

Gilson HPLC with Gilson UV-VIS-155 Detektor, 231 XL sampling injector.

The wavelength given is the substance-specific UV maximum.

A: water with 0.1% ammonia 35%

B: acetonitrile

time in min % A % B flow rate in ml/min  0.00 95 5 180  1.40 95 5 18017.00 2 98 180 18.50 2 98 180 18.70 95 5 180 20.-50 95 5 180

The stationary phase used is a Pursuit XRS RP 18 column, 10 μm, 50×150mm, ambient temperature.

Preparative HPLC, method B

Gilson HPLC with Gilson UV-VIS-155 detector, 231 XL sampling injector.

The wavelength given is the substance-specific UV maximum.

A: water with 0.13% TFA

B: acetonitrile with 0.1% TFA

time in min % A % B flow rate in ml/min 0.00 95 5 165 1.30 95 5 165 8.902 98 165 10.00 2 98 165 10.50 95 5 165 11.60 95 5 165

The stationary phase used is a Microsorb RP 18 column, 8 μm, 50×65 mm,ambient temperature.

Indications

As has been found, the combinations according to the inventioncontaining a compound of formula 1 and at least one NSAID arecharacterised by their wide range of applications in the therapeuticfield. Particular mention should be made of those applications for whichthe combinations according to the invention are preferably suited onaccount of their pharmaceutical efficacy as PDE4 inhibitors. Examplesinclude respiratory or gastrointestinal diseases or complaints,inflammatory diseases of the joints, skin or eyes, cancers, and alsodiseases of the peripheral or central nervous system.

Particular mention should be made of the prevention and treatment ofdiseases of the airways and of the lung which are accompanied byincreased mucus production, inflammations and/or obstructive diseases ofthe airways. Examples include acute, allergic or chronic bronchitis,chronic obstructive bronchitis (COPD), coughing, pulmonary emphysema,allergic or non-allergic rhinitis or sinusitis, chronic rhinitis orsinusitis, asthma, alveolitis, Farmer's disease, hyperreactive airways,infectious bronchitis or pneumonitis, paediatric asthma, bronchiectases,pulmonary fibrosis, ARDS (acute adult respiratory distress syndrome),bronchial oedema, pulmonary oedema, bronchitis, pneumonia orinterstitial pneumonia triggered by various causes, such as aspiration,inhalation of toxic gases, or bronchitis, pneumonia or interstitialpneumonia as a result of heart failure, irradiation, chemotherapy,cystic fibrosis or mucoviscidosis, or alpha1-antitrypsin deficiency.

Also deserving special mention is the treatment of inflammatory diseasesof the gastrointestinal tract. Examples include acute or chronicinflammatory changes in gall bladder inflammation, Crohn's disease,ulcerative colitis, inflammatory pseudopolyps, juvenile polyps, colitiscystica profunda, pneumatosis cystoides intestinales, diseases of thebile duct and gall bladder, e.g. gallstones and conglomerates, for thetreatment of inflammatory diseases of the joints such as rheumatoidarthritis or inflammatory diseases of the skin and eyes.

Preferential mention should also be made of the treatment of cancers.Examples include all forms of acute and chronic leukaemias such as acutelymphatic and acute myeloid leukaemia, chronic lymphatic and chronicmyeloid leukaemia, and bone tumours such as osteosarcoma and all typesof glioma such as oligodendroglioma and glioblastoma.

Preferential mention should also be made of the prevention and treatmentof diseases of the peripheral or central nervous system. Examples ofthese include depression, bipolar or manic depression, acute and chronicanxiety states, schizophrenia, Alzheimer's disease, Parkinson's disease,acute and chronic multiple sclerosis or acute and chronic pain as wellas injuries to the brain caused by stroke, hypoxia or craniocerebraltrauma.

Particularly preferably the present invention relates to the use of thecombinations according to the invention for preparing a medicament forthe treatment of inflammatory or obstructive diseases of the upper andlower respiratory tract including the lungs, such as for exampleallergic rhinitis, chronic rhinitis, bronchiectasis, cystic fibrosis,idiopathic pulmonary fibrosis, fibrosing alveolitis, COPD, chronicbronchitis, chronic sinusitis, asthma, Crohn's disease, ulcerativecolitis, particularly COPD, chronic bronchitis and asthma.

It is most preferable to use the combinations according to the inventionfor the treatment of inflammatory and obstructive diseases such as COPD,chronic bronchitis, chronic sinusitis, asthma, Crohn's disease,ulcerative colitis, particularly COPD, chronic bronchitis and asthma.

It is also preferable to use the combinations according to the inventionfor the treatment of diseases of the peripheral or central nervoussystem such as depression, bipolar or manic depression, acute andchronic anxiety states, schizophrenia, Alzheimer's disease, Parkinson'sdisease, acute and chronic multiple sclerosis, amyotrophic lateralsclerosis (ALS) or acute and chronic pain as well as injuries to thebrain caused by stroke, hypoxia or craniocerebral trauma.

An outstanding aspect of the formulations according to the inventioncontaining a combination of a compound of formula 1 and at least oneNSAID is the reduced profile of side effects compared with formulationsthat contain the same compound of formula 1 in the same amount in theabsence of an NSAID. Side effects that frequently occur when taking aPDE4 inhibitor preferentially include, inter alia, diarrhoea, nausea andvomiting. In the rat model further side effects were observed after theadministration of PDE4 inhibitor, such as for example weight loss,leukocytosis and neutrophilia, as well as diarrhoea.

By a reduced profile of side effects is meant, within the scope of theinvention, in particular being able to administer a therapeuticallyeffective dose of a PDE4 inhibitor in a pharmaceutical compositionaccording to the invention without inducing to any appreciable extent inthe patient the or at least one of the side effects commonly observedwhen PDE4 inhibitors are administered. It is particularly preferable toadminister a therapeutically effective amount of a PDE4 inhibitor in thecomposition according to the invention at every stage of the course ofthe disease without triggering the typical PDE4 inhibitor-mediated sideeffects of diarrhoea, weight loss, leukocytosis or neutrophilia. In aparticular aspect the present invention relates to the administration ofa therapeutically effective amount of the pharmaceutical compositionaccording to the invention at every stage of the course of the diseasewithout triggering the typical PDE4 inhibitor-mediated side effect ofdiarrhoea to any appreciable degree.

Experiments on the rat model described hereinafter show that thepharmaceutical compositions according to the invention containing a PDE4inhibitor and at least one NSAID substantially reduce or even totallyprevent many of the side effects which occur when the corresponding PDE4inhibitor is administered on its own.

EXPERIMENTAL METHOD

The results of the following experiments are summarized in the Figures:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows the body weights of the rats from the different groups(control group, Roflumilast group, Roflumilast+Diclofenac group andDiclofenac group) as a percentage change from the time of the firstadministration (=day 1, 0800 hours (=time t₀)). The average±standarddeviation of the body weights at time t0 was 355±17 g.

FIG. 1B shows the measured white blood cells (left side) and themeasured neutrophils (right side) for the different groups (controlgroup, Roflumilast group, Roflumilast+Diclofenac group and Diclofenacgroup). Statistics: One-way analysis of variance; ns=not significant;***=p<0.001.

FIG. 2A shows the body weights of the rats from the different groups(control group, Roflumilast group, Roflumilast+SC-560 group,Roflumilast+Lumiracoxib group, SC-560 group and Lumiracoxib group) as apercentage change from the time of the first administration (=day 1,0800 hours (=time t₀)). The average±standard deviation of the bodyweights at time t₀ was 306±11 g.

FIG. 2B shows the measured white blood cells (left side) and themeasured neutrophils (right side) for the different groups (controlgroup, Roflumilast group, Roflumilast+SC-560 group,Roflumilast+Lumiracoxib group, SC-560 group and Lumiracoxib group).Statistics: One-way analysis of variance; ns=not significant; *=p<0.05;***=p<0.001.

Experiment 1 Diclofenac Provides Protection Against Roflumilast-MediatedEffects Such as Weight Loss, Leukocytosis, and Neutrophilia

Six male Wistar rats in each group were treated for four days with thefollowing substances (all substances are given p.o.=orally):

Group 1 (“control group”): Six male Wistar rats were given a daily doseof 0.5% Natrosol (placebo) at the times 0800, 1300 and 1700 hours.

Group 2 (“roflumilast group”): Six male Wistar rats were given a dailydose of 0.5% Natrosol (placebo) at 0800 and 1700 hours and 10 mg/kgroflumilast (PDE4 inhibitor) at 1300 hours.

Group 3 (“roflumilast+diclofenac group”): Six male Wistar rats weregiven a daily dose of 1 mg/kg diclofenac (NSAID) at the times 0800 and1700 hours and 10 mg/kg roflumilast (PDE4 inhibitor) at 1300 hours.

Group 4 (“diclofenac group”): Six male Wistar rats were given a dailydose of 1 mg/kg diclofenac (NSAID) at the times 0800 and 1700 hours and0.5% Natrosol (placebo) at 1300 hours.

For pharmacokinetic analysis (determining the plasma levels of thesubstances) on day 4 one rate from each group was used; these rats wereno longer available for other parameters under investigation. The sameapplied to one rat from the roflumilast group which died between day 4and day 5 of the experiment.

FIG. 1A shows the body weights of the rats from the different groups asa percentage change from the time of the first administration (=day 1,0800 hours (=time t₀)). The average±standard deviation of the bodyweights at time t₀ was 355±17 g.

At the end of the experiment (95 hours after t₀ (=the time of the firstadministration on day 1, 0800)) the proportion of white blood cells(×1000 cells/μl blood, FIG. 1B, left-hand Figure) and the proportion ofneutrophils (in % of white blood cells, FIG. 1B, right-hand Figure) weredetermined from the blood of 4 or 5 of the rats from the individualgroups.

Experiment 2 Diclofenac Provides Protection Against Roflumilast-MediatedEffects such as Diarrhoea

Six male Wistar rats in each group were treated for four days with thefollowing substances (all substances are given p.o.=orally):

Group 1 (“control group”): Six male Wistar rats were given a daily doseof 0.5% Natrosol (placebo) at the times 0800, 1300 and 1700 hours.

Group 2 (“roflumilast group”): Six male Wistar rats were given a dailydose of 0.5% Natrosol (placebo) at 0800 and 1700 hours and 10 mg/kgroflumilast (PDE4 inhibitor) at 1300 hours.

Group 3 (“roflumilast+diclofenac group”): Six male Wistar rats weregiven a daily dose of 1 mg/kg diclofenac (NSAID) at the times 0800 and1700 hours and 10 mg/kg roflumilast (PDE4 inhibitor) at 1300 hours.

Group 4 (“diclofenac group”): Six male Wistar rats were given a dailydose of 1 mg/kg diclofenac (NSAID) at the times 0800 and 1700 hours and0.5% Natrosol (placebo) at 1300 hours.

For pharmacokinetic analysis (determining the plasma levels of thesubstances) on day 4 one rat from each group was used; these rats wereno longer available for other parameters under investigation. The sameapplied to one rat from the roflumilast group which died between day 4and day 5 of the experiment.

At the end of the experiment (95 hours after t₀ (=the time of the firstadministration on day 1, 0800 hours)) the rats from the individualgroups were examined phenotypically and histopathologically for thepresence of multifocal perivascular mononuclear infiltration(=inflammation parameter) in the mesentery and for the proliferation offibroblasts in the mesentery. In addition, the occurrence of diarrhoeain the rats from the different groups was noted. The findings aresummarised in Table 1 as follows:

TABLE 1 Phenotypical and histopathological findings roflumilast +Control roflumilast diclofenac diclofenac Parameter (group 1) (group 2)(group 3) (group 4) Diarrhoea 0/6 (=0 5/6 0/6 0/6 out of 6 animals)Mesentery: multifocal 0/5 4/4 0/5 0/5 perivascular mononuclearinfiltration (=inflammation parameter) Mesentery: 0/5 4/4 0/5 0/5Proliferation of fibroblasts

To summarise, it can be stated that the PDE4 inhibitor-mediated sideeffects such as weight loss (FIG. 1A), leukocytosis (FIG. 1B, on theleft), neutrophilia (FIG. 1B, on the right) and diarrhoea (including thepresence of inflammation parameters and the proliferation of fibroblastsin the mesentery) observed in the roflumilast group can be substantiallyreduced or prevented (often even reduced to the level found in thecontrol group), by co-administering an NSAID such as diclofenac (cf.roflumilast+diclofenac group) simultaneously or only a few hours apart.The parameters measured after the administration of diclofenac alonewere found to be very similar to the control groups.

Experiment 3 The COX-2 Selective Inhibitor Lumiracoxib, but Not theCOX-1 Selective Inhibitor SC-560, Provides Protection fromRoflumilast-Mediated Effects such as Weight Loss, Leukocytosis andNeutrophilia

Six male Wistar rats in each group were treated for four days with thefollowing substances (all substances are given p.o.=orally):

Group 1 (“control group”): Six male Wistar rats were given a daily doseof 0.5% Natrosol (placebo) at the times 0800, 1300 and 1700 hours.

Group 2 (“roflumilast group”): Six male Wistar rats were given a dailydose of 0.5% Natrosol (placebo) at 0800 and 1700 hours and 10 mg/kgroflumilast (PDE4 inhibitor) at 1300 hours.

Group 3 (“roflumilast+SC-560 group”): Six male Wistar rats were given adaily dose of 2 mg/kg SC-560 (NSAID, selective for COX-1) at the times0800 and 1700 hours and 10 mg/kg roflumilast (PDE4 inhibitor) at 1300hours.

Group 4 (“roflumilast+lumiracoxib group”): Six male Wistar rats weregiven a daily dose of 2 mg/kg lumiracoxib (NSAID, selective for COX-2)at the times 0800 and 1700 hours and 10 mg/kg of reflumilast (PDE4inhibitor) at 1300 hours.

Group 5 (“SC-560 group”): Six male Wistar rats were given a daily doseof 2 mg/kg SC-560 (NSAID, selective for COX-1) at the times 0800 and1700 hours and 0.5% Natrosol at 1300 hours.

Group 6 (“lumiracoxib group”): Six male Wistar rats were given a dailydose of 2 mg/kg lumiracoxib (NSAID, selective for COX-2) at the times0800 and 1700 hours and 0.5% Natrosol at 1300 hours.

For pharmacokinetic analysis (determining the plasma levels of thesubstances) on day 4 one rat from each group was used; these rats wereno longer available for other parameters under investigation.

FIG. 2A shows the body weights of the rats from the different groups asa percentage change from the time of the first administration (=day 1,0800 hours (=time t₀)). The average±standard deviation of the bodyweights at time t₀ was 306±11 g.

At the end of the experiment (95 hours after t₀ (=the time of the firstadministration on day 1, 0800 hours)) the proportion of white bloodcells (×1000 cells/μl blood, FIG. 3B, left-hand Figure) and theproportion of neutrophils (in % of white blood cells, FIG. 3B,right-hand Figure) were determined from the blood of 5 of the rats fromthe individual groups.

Experiment 4 The COX-2 Selective Inhibitor Lumiracoxib, but Not theCOX-1 Selective Inhibitor SC-560, Provides Protection fromRoflumilast-Mediated Effects such as Diarrhoea

Six male Wistar rats in each group were treated for four days with thefollowing substances (all substances are given p.o.=orally):

Group 1 (“control group”): Six male Wistar rats were given a daily doseof 0.5% Natrosol (placebo) at the times 0800, 1300 and 1700 hours.

Group 2 (“roflumilast group”): Six male Wistar rats were given a dailydose of 0.5% Natrosol (placebo) at 0800 and 1700 hours and 10 mg/kgroflumilast (PDE4 inhibitor) at 1300 hours.

Group 3 (“roflumilast+SC-560 group”): Six male Wistar rats were given adaily dose of 2 mg/kg SC-560 (NSAID, selective for COX-1) at the times0800 and 1700 hours and 10 mg/kg roflumilast (PDE4 inhibitor) at 1300hours.

Group 4 (“roflumilast+lumiracoxib group”): Six male Wistar rats weregiven a daily dose of 2 mg/kg lumiracoxib (NSAID, selective for COX-2)at the times 0800 and 1700 hours and 10 mg/kg of roflumilast (PDE4inhibitor) at 1300 hours.

Group 5 (“SC-560 group”): Six male Wistar rats were given a daily doseof 2 mg/kg SC-560 (NSAID, selective for COX-1) at the times 0800 and1700 hours and 0.5% Natrosol at 1300 hours.

Group 6 (“lumiracoxib group”): Six male Wistar rats were given a dailydose of 2 mg/kg lumiracoxib (NSAID, selective for COX-2) at the times0800 and 1700 hours and 0.5% Natrosol at 1300 hours. For pharmacokineticanalysis (determining the plasma levels of the substances) on day 4 onerat from each group was used; these rats were no longer available forother parameters under investigation.

At the end of the experiment (95 hours after t₀ (=the time of the firstadministration on day 1, 0800 hours)) the rats from the individualgroups were examined phenotypically and histopathologically for thepresence of multifocal perivascular mononuclear infiltration(=inflammation parameter) in the mesentery and for the proliferation offibroblasts in the mesentery. In addition, the occurrence of diarrhoeain the rats from the different groups was noted. The findings aresummarised in Table 2 as follows:

TABLE 2 Phenotypical and histopathological findings roflumilast +roflumilast + control roflumilast SC-560 lumiracoxib SC-560 lumiracoxibParameter (group 1) (group 2) (group 3) (group 4) (group 5) (group 6)Diarrhoea 0/6 (=0 2/6 0/6 0/6 0/6 0/6 von 6 Tieren) Mesentery: 0/5 5/54/5 0/5 0/5 0/5 multifocal perivascular mononuclear infiltration(=inflammation parameter) Mesentery: 0/5 5/5 4/5 0/5 0/5 0/5Proliferation of fibroblasts

To summarise, it can be stated that the PDE4 inhibitor-mediated sideeffects such as weight loss (FIG. 2A), leukocytosis (FIG. 2B, on theleft), neutrophilia (FIG. 2B, on the right) and diarrhoea (including thepresence of inflammation parameters and the proliferation of fibroblastsin the mesentery) observed in the roflumilast group can be substantiallyreduced or prevented (often even reduced to the level found in thecontrol group), by co-administering a COX-2 selective NSAID such aslumiracoxib (cf. roflumilast+lumiracoxib) simultaneously or only a fewhours apart. The COX-1 selective NSAID SC-560 has absolutely noprotective effect on weight loss, leukocytosis and neutrophilia and onlya very slight protective effect on the histopathological findings(multifocal perivascular mononuclear infiltration or proliferation offibroblasts in the mesentery). It is difficult to make anypronouncements as to the effect of SC-560 on diarrhoea because in thisexperiment, in the roflumilast group, diarrhoea was only found per se intwo animals (as a rule, an even greater percentage of the animalsexhibit diarrhoea after the administration of roflumilast). Theparameters measured after the administration of SC-560 or lumiracoxibalone were found to be very similar to the control groups.

To sum up, it can be concluded that the protective effect of an NSAID onthe PDE4 inhibitor-mediated side effects are based on the inhibition ofCOX-2.

Formulations

The active substance combinations of 1 and 2 are preferably administeredorally. For this purpose the ingredients (1) and (2) have to bepresented in suitable oral preparations.

Suitable oral forms for administration are for example tablets,capsules, solutions, syrups or emulsions. The content of thepharmaceutically effective compound(s) in each case should be in therange from 0.1 to 90 wt. %, preferably 0.5 to 50 wt. % of the totalcomposition, i.e. in amounts which are sufficient to achieve the dosagerange specified hereinafter.

The preparations may be administered orally in the form of a tablet, asa powder, as a powder in a capsule (e.g. a hard gelatine capsule), as asolution or suspension.

It is particularly preferable if the preparations are administered onceor twice a day. Suitable tablets may be obtained, for example, by mixingthe active substance(s) with known excipients, for example inertdiluents such as calcium carbonate, calcium phosphate, microcrystallinecellulose, sorbitol, mannitol, isomaltose or lactose, disintegrants suchas corn starch, crosslinked polyvinyl pyrrolidone, crosslinked sodiumcarboxymethylcellulose, sodium starch glycolate or alginic acid, binderssuch as starch, hydroxypropylmethylcellulose, polyvinylpyrrolidone orgelatine, lubricants, such as magnesium stearate or talc, and/or agentsfor delaying release, such as hydroxypropylcellulose,hydroxypropylmethylcellulose, ethylcellulose, aminomethacrylate,polyvinylpyrrolidone-polyvinylacetate copolymer, carboxymethylcelluloseor polyvinylacetate. The tablets may also comprise several layers.

Coated tablets or film-coated tablets may be prepared accordingly bycoating cores produced analogously to the tablets with substancesnormally used for tablet or film coatings, for example collidone orshellac, gum arabic, talc, titanium dioxide, sugar, hydroxypropylmethylcellulose, ethycellulose, cellulose acetate phthalate, polymethacrylate,polyethyleneglycol, polyvinylalcohol,polyvinylalcohol-polyethyleneglycol copolymers or polyvinylacetate. Toachieve delayed release or prevent incompatibilities the core may alsoconsist of a number of layers. Similarly the tablet coating may consistof a number of layers to achieve delayed release, possibly using theexcipients mentioned above for the tablets.

Syrups containing the active substances or combinations thereofaccording to the invention may additionally contain a sweetener such assaccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. aflavouring such as vanillin or orange extract. They may also containsuspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

For oral administration the tablets may, of course, contain, apart fromthe abovementioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulphate and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavour enhancers or colourings in addition to the excipients mentionedabove.

Examples of Formulations:

The following formulation examples for combined formulations areintended to serve to illustrate the invention without restricting itthereto. In particular, the active substances 1 and 2 may also bepresent in separate formulations and administered separately within atime window of not more than 6 hours.

1) 0.05 mg active substance 1 500 mg acetylsalicylic acid (activesubstance 2) 100 mg lactose 329.95 mg microcrystalline cellulose 30 mgpolyvinylpyrrolidone 30 mg crosslinked polyvinylpyrrolidone 10 mgmagnesium stearate 1000 mg 2) 0.1 mg active substance 1 500 mgacetylsalicylic acid (active substance 2) 100 mg lactose 329.9 mgmicrocrystalline cellulose 30 mg crosslinked polyvinylpyrrolidone 30 mgpolyvinylpyrrolidone 10 mg magnesium stearate 1000 mg 3) 0.5 mg activesubstance 1 500 mg acetylsalicylic acid (active substance 2) 100 mglactose 329.5 mg microcrystalline cellulose 30 mg crosslinkedpolyvinylpyrrolidone 30 mg polyvinylpyrrolidone 10 mg magnesium stearate1000 mg 4) 5 mg active substance 1 500 mg acetylsalicylic acid (activesubstance 2) 100 mg lactose 325 mg microcrystalline cellulose 30 mgcrosslinked polyvinylpyrrolidone 30 mg polyvinylpyrrolidone 10 mgmagnesium stearate 1000 mg 5) 20 mg active substance 1 500 mgacetylsalicylic acid (active substance 2) 100 mg lactose 310 mgmicrocrystalline cellulose 30 mg crosslinked polyvinylpyrrolidone 30 mgpolyvinylpyrrolidone 10 mg magnesium stearate 1000 mg 6) 0.05 mg activesubstance 1 25 mg diclofenac (active substance 2) 170 mg lactose 269.95mg microcrystalline cellulose 15 mg crosslinked polyvinylpyrrolidone 15mg polyvinylpyrrolidone 5 mg magnesium stearate 500 mg 7) 0.1 mg activesubstance 1 25 mg diclofenac (active substance 2) 170 mg lactose 269.9mg microcrystalline cellulose 15 mg crosslinked polyvinylpyrrolidone 15mg polyvinylpyrrolidone 5 mg magnesium stearate 500 mg 8) 0.5 mg activesubstance 1 25 mg diclofenac (active substance 2) 170 mg lactose 269.5mg microcrystalline cellulose 15 mg crosslinked polyvinylpyrrolidone 15mg polyvinylpyrrolidone 5 mg magnesium stearate 500 mg 9) 5 mg activesubstance 1 25 mg diclofenac (active substance 2) 170 mg lactose 265 mgmicrocrystalline cellulose 15 mg crosslinked polyvinylpyrrolidone 15 mgpolyvinylpyrrolidone 5 mg magnesium stearate 500 mg 10) 20 mg activesubstance 1 25 mg diclofenac (active substance 2) 170 mg lactose 240 mgmicrocrystalline cellulose 15 mg crosslinked polyvinylpyrrolidone 15 mgpolyvinylpyrrolidone 5 mg magnesium stearate 500 mg 11) 0.05 mg activesubstance 1 15 mg meloxicam (active substance 2) 170 mg lactose 279.95mg microcrystalline cellulose 15 mg crosslinked polyvinylpyrrolidone 15mg polyvinylpyrrolidone 5 mg magnesium stearate 500 mg 12) 0.1 mg activesubstance 1 15 mg meloxicam (active substance 2) 170 mg lactose 279.9 mgmicrocrystalline cellulose 15 mg crosslinked polyvinylpyrrolidone 15 mgpolyvinylpyrrolidone 5 mg magnesium stearate 500 mg 13) 0.5 mg activesubstance 1 15 mg meloxicam (active substance 2) 170 mg lactose 279.5 mgmicrocrystalline cellulose 15 mg crosslinked polyvinylpyrrolidone 15 mgpolyvinylpyrrolidone 5 mg magnesium stearate 500 mg 14) 5 mg activesubstance 1 15 mg meloxicam (active substance 2) 170 mg lactose 275 mgmicrocrystalline cellulose 15 mg crosslinked polyvinylpyrrolidone 15 mgpolyvinylpyrrolidone 5 mg magnesium stearate 500 mg 15) 20 mg activesubstance 1 15 mg meloxicam (active substance 2) 170 mg lactose 260 mgmicrocrystalline cellulose 15 mg crosslinked polyvinylpyrrolidone 15 mgpolyvinylpyrrolidone 5 mg magnesium stearate 500 mg 16) 0.05 mg activesubstance 1 500 mg naproxen (active substance 2) 100 mg lactose 329.95mg microcrystalline cellulose 30 mg crosslinked polyvinylpyrrolidone 30mg polyvinylpyrrolidone 10 mg magnesium stearate 1000 mg 17) 0.1 mgactive substance 1 500 mg naproxen (active substance 2) 100 mg lactose329.9 mg microcrystalline cellulose 30 mg crosslinkedpolyvinylpyrrolidone 30 mg polyvinylpyrrolidone 10 mg magnesium stearate1000 mg 18) 0.5 mg active substance 1 500 mg naproxen (active substance2) 100 mg lactose 329.5 mg microcrystalline cellulose 30 mg crosslinkedpolyvinylpyrrolidone 30 mg polyvinylpyrrolidone 10 mg magnesium stearate1000 mg 19) 5 mg active substance 1 500 mg naproxen (active substance 2)100 mg lactose 325 mg microcrystalline cellulose 30 mg crosslinkedpolyvinylpyrrolidone 30 mg polyvinylpyrrolidone 10 mg magnesium stearate1000 mg 20) 20 mg active substance 1 500 mg naproxen (active substance2) 100 mg lactose 310 mg microcrystalline cellulose 30 mg crosslinkedpolyvinylpyrrolidone 30 mg polyvinylpyrrolidone 10 mg magnesium stearate1000 mg 21) 0.05 mg active substance 1 200 mg ibuprofen (activesubstance 2) 100 mg lactose 258.95 mg microcrystalline cellulose 18 mgcrosslinked polyvinylpyrrolidone 18 mg polyvinylpyrrolidone 5 mgmagnesium stearate 600 mg 22) 0.1 mg active substance 1 200 mg ibuprofen(active substance 2) 100 mg lactose 258.9 mg microcrystalline cellulose18 mg crosslinked polyvinylpyrrolidone 18 mg polyvinylpyrrolidone 5 mgmagnesium stearate 600 mg 23) 0.5 mg active substance 1 200 mg ibuprofen(active substance 2) 100 mg lactose 258.5 mg microcrystalline cellulose18 mg crosslinked polyvinylpyrrolidone 18 mg polyvinylpyrrolidone 5 mgmagnesium stearate 600 mg 24) 5 mg active substance 1 200 mg ibuprofen(active substance 2) 100 mg lactose 254 mg microcrystalline cellulose 18mg crosslinked polyvinylpyrrolidone 18 mg polyvinylpyrrolidone 5 mgmagnesium stearate 600 mg 25) 20 mg active substance 1 200 mg ibuprofen(active substance 2) 100 mg lactose 239 mg microcrystalline cellulose 18mg crosslinked polyvinylpyrrolidone 18 mg polyvinylpyrrolidone 5 mgmagnesium stearate 600 mg

The finely ground active substance, lactose and some of themicrocrystalline cellulose are mixed together. The mixture is screened,then moistened with a solution of polyvinylpyrrolidone in water,kneaded, wet-granulated and dried. The granules, the rest of themicrocrystalline cellulose and the crosslinked polyvinylpyrrolidone arescreened and mixed together. Then the magnesium stearate is screened inand briefly mixed in. The mixture is compressed to form tablets ofsuitable shape and size.

The invention claimed is:
 1. A method of treating a disease selectedfrom respiratory complaints, pulmonary diseases, gastrointestinalailments and diseases, inflammatory diseases of the joints, skin, oreyes, cancers, and diseases of the peripheral or central nervous system,the method comprising administering to a patient in need thereof aneffective amount of: (a) a PDE4 inhibitor of formula 1

wherein: X is SO or SO₂; R¹ is H or C₁₋₆-alkyl; R² is H or a groupselected from C₁₋₁₀-alkyl and C₂₋₆-alkenyl, each optionally substitutedby one or more groups selected from halogen and C₁₋₃-fluoroalkyl oroptionally substituted by one or more groups selected from OR^(2.1),COOR^(2.1), CONR^(2.2)R^(2.3), SR^(2.1), SO—R^(2.1), SO₂—R^(2.1),C₆₋₁₀-aryl, het, hetaryl, a mono- or bicyclic C₃₋₁₀-cycloalkyl,CH₂—NR^(2.2)R^(2.3), and NR^(2.2)R^(2.3), which in turn is optionallysubstituted by one or more groups selected from OH, halogen, OR^(2.1),oxo, CF₃, CHF₂, CH₂F, C₁₋₆-alkyl, C₁₋₆-alkanol, C₆₋₁₀-aryl, COOR^(2.1),CH₂—NR^(2.2)R^(2.3), and NR^(2.2)R^(2.3), R² is a mono- or polycyclicC₃₋₁₀ cycloalkyl optionally singly or multiply bridged by C₁₋₃-alkylgroups and optionally substituted by a group selected from branched orunbranched C₁₋₆-alkanol, C₁₋₃-fluoroalkyl, C₁₋₃-alkylene-OR^(2.1),OR^(2.1), COOR^(2.1, SO) ₂—NR^(2.2)R^(2.3), het, C₆₋₁₀-aryl, C₁₋₆-alkyl,C₆₋₁₀-aryl-C₁₋₆-alkylene, hetaryl-C₁₋₆-alkylene, mono- or bicyclic C₃₋₁₀cycloalkyl, and NR^(2.2)R^(2.3), each of which is optionally substitutedby one or more groups selected from OH, OR^(2.1), oxo, halogen, CF₃,CHF₂, CH₂F, C₁₋₆-alkyl, C₆₋₁₀-aryl, and NR^(2.2)R^(2.3), R² is a mono-or polycyclic C₆₋₁₀-aryl optionally substituted by OH, SH, or halogen orby one or more groups selected from OR^(2.1), COOR^(2.1),NR^(2.2)R^(2.3), CH₂—NR^(2.2)R^(2.3), C₃₋₁₀-cycloalkyl, het,—C₁₋₆-alkyl, C₁₋₃-fluoroalkyl, C₆₋₁₀-aryl-C₁₋₆-alkylene,het-C₁₋₆-alkylene, hetaryl-C₁₋₆-alkylene, C₆₋₁₀-aryl, SO₂—CH₃,SO₂—CH₂CH₃, and SO₂—NR^(2.2)R^(2.3), each of which in turn is optionallysubstituted by one or more groups selected from OH, OR^(2.1), CF₃, CHF₂,CH₂F, oxo, halogen, CF₃, CHF₂, CH₂F, C₁₋₆-alkyl, C₆₋₁₀-aryl, andNR^(2.2)R^(2.3), R² is a group selected from het and hetaryl, eachoptionally substituted by one or more groups selected from halogen, OH,oxo, CF₃, CHF₂, and CH₂F or by one or more groups selected fromOR^(2.1), C₁₋₃-alkylene-OR^(2.1), SR^(2.1), SO—R^(2.1) and SO₂—R^(2.1),COOR^(2.1), COR^(2.1), C₁₋₆-alkanol, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl,C₁₋₆-alkyl, C₆₋₁₀-aryl-C₁₋₆-alkylene, hetaryl-C₁₋₆-alkylene, het,hetaryl, C₁₋₃-alkylene-OR^(2.1), and NR^(2.2)R^(2.3), each of which inturn is optionally substituted by one or more groups selected from OH,OR^(2.1), oxo, halogen, CF₃, CHF₂, CH₂F, C₁₋₆-alkyl, C₆₋₁₀-aryl, andNR^(2.2)R^(2.3), or NR¹R² together is a heterocyclic four- toseven-membered ring optionally bridged, which contains 1, 2, or 3heteroatoms selected from N, O, and S, and which is optionallysubstituted by one or more groups selected from OH, OR^(2.1),C₁₋₃-alkylene-O^(R.1), oxo, halogen, C₁₋₆-alkyl, C₆₋₁₀-aryl, COOR^(2.1),CH₂—NR^(2.2)—COO—R^(2.1), CH₂—NR^(2.2)—CO—R^(2.1),CH₂—NR^(2.2)—CO—CH₂—NR^(2.2)R^(2.3), CH₂—NR^(2.2)—SO₂—C₁₋₃-alkyl,CH₂—NR^(2.2)—SO₂—NR^(2.2)R^(2.3), CH₂—NR^(2.2)—CO—NR^(2.2)R^(2.3),CO—NR^(2.2)R^(2.3), CH₂—NR^(2.2)R^(2.3), and N^(R2.2)R^(2.3); and R³ isa group selected from het and hetaryl, each optionally substituted byone or more groups selected from halogen, C₁₋₃-fluoroalkyl, CN, OH, oxo,—C₁₋₆-alkyl, —O—R^(2.1), —COOR^(2.1), SO—R^(2.1), SO₂—R^(2.1),C₆₋₁₀-aryl, C₁₋₃-alkylene-C₆₋₁₀-aryl, —C₁₋₃-alkylene-NR^(2.2)R^(2.3),—NR^(2.2)R^(2.3), a C₃₋₁₀-cycloalkyl, a C₁₋₃-alkylene-C₃₋₁₀-cycloalkyl,a het, a hetaryl, C₁₋₃-alkylene-hetaryl, and C₁₋₃-alkylene-het, each ofwhich in turn is optionally substituted by one or more groups selectedfrom OH, halogen, —C₁₋₃-fluoroalkyl, C₁₋₆-alkyl, C₆₋₁₀-aryl,—COO(C₁₋₃-alkyl), and O—(C₁₋₃-alkyl), and wherein: het is a three- toeleven-membered, mono- or bicyclic, saturated or partly saturated,optionally annelated or optionally bridged heterocyclic group whichcontains 1, 2, 3, or 4 heteroatoms independently selected from N, S, orO, hetaryl is a five- to eleven-membered, mono- or bicyclic, optionallyannelated heteroaryl which contains 1, 2, 3, or 4 heteroatomsindependently selected from N, S, or O, cycloalkyl is saturated orpartly saturated, R^(2.1) is H or a group selected from C₁₋₆-alkyl,C₁₋₆-alkanol, C₁₋₃-haloalkyl, mono- or bicyclic C₃₋₁₀-cycloalkyl,C₆₋₁₀-aryl-C₁₋₆-alkylene, mono- or bicyclic hetaryl-C₁₋₆-alkylene,het-C₁₋₆-alkylene, C₃₋₁₀-cycloalkyl-C₁₋₆-alkylene, a mono- or bicyclicC₆₋₁₀-aryl, hetaryl, and het, each optionally substituted by one or moregroups selected from OH, O—(C₁₋₃-alkyl), halogen, C₁₋₆-alkyl, andC₆₋₁₀-aryl, and R^(2.2) and R^(2.3) are each independently H or a groupselected from C₁₋₆-alkyl, mono- or bicyclic C₃₋₁₀ cycloalkyl,C₆₋₁₀-aryl-C₁₋₆-alkylene, hetaryl-C₁₋₆-alkylene, mono- or bicyclicC₆₋₁₀-aryl, het, hetaryl, CO—NH₂, CO—NHCH₃, CO—N(CH₃)₂,SO₂—(C₁-C₂-alkyl), CO—R^(2.1), and COOR^(2.1), each optionallysubstituted by one or more groups selected from OH, halogen, C₁₋₆-alkyl,C₆₋₁₀-aryl and COOR^(2.1), and (b) an NSAID.
 2. The method according toclaim 1, wherein for the PDE4 inhibitor of formula 1: X is SO; R¹ is H;R² is H or C₁₋₆-alkyl optionally substituted by one or more groupsselected from F, CF₃, CHF₂, or CH₂F or optionally substituted by one ormore groups selected from OR²COOR^(2.1), CONR^(2.2)R^(2.3), SR^(2.1),SO—R^(2.1), SO₂—R^(2.1), phenyl, het, hetaryl, a monocyclicC₃₋₇-cycloalkyl, CH₂—NR^(2.2)R^(2.3), and NR^(2.2)R^(2.3), each of whichin turn is optionally substituted by one or more groups selected fromOH, F, Cl, Br, CF₃, CHF₂, CH₂F, OR^(2.1), oxo, methyl, ethyl, propyl,isopropyl, C₁₋₂-alkanol, phenyl, COOR^(2.1), CH₂—NR^(2.2)R^(2.3), andNR^(2.2)R^(2.3), R² is a monocyclic C₃₋₇ cycloalkyl, which mayoptionally be substituted by a group selected from branched orunbranched C₁₋₂-alkanol, C₁₋₃-fluoroalkyl, C₁₋₃-alkylene-OR^(2.1),OR^(2.1), COOR^(2.1), SO₂—NR^(2.2)R^(2.3), het, methyl, ethyl, propyl,isopropyl, phenyl, phenyl-C₁₋₂-alkylene, hetaryl-C₁₋₂-alkylene,monocyclic C₃₋₇ cycloalkyl, and NR^(2.2)R^(2.3), which may optionally besubstituted by one or more groups selected from OH, OR^(2.1), oxo,halogen, CF₃, CHF₂, CH₂F, methyl, ethyl, propyl, isopropyl, phenyl, andNR^(2.2)R^(2.3), or R² is a phenyl, which may optionally be substitutedby OH, SH, F, Cl or Br or by one or more groups selected from OR^(2.1),COOR^(2.1), NR^(2.2)R^(2.3), CH₂—NR^(2.2)R^(2.3), C₃₋₇-cycloalkyl, het,methyl, ethyl, propyl, isopropyl, CF₃, CHF₂, CH₂F, phenyl-C₁₋₂-alkylene,het-C₁₋₂-alkylene, hetaryl-C₁₋₂-alkylene, phenyl, SO₂—CH₃, SO₂—CH₂CH₃and SO₂—NR^(2.2)R^(2.3), which in turn may optionally be substituted byone or more groups selected from OH, OR^(2.1), oxo, F, Cl, Br, CF₃,CHF₂, CH₂F, methyl, ethyl, propyl, isopropyl, phenyl andNR^(2.2)R^(2.3), or R² is a group selected from het and hetaryl, whichmay optionally be substituted by one or more groups selected from F, Cl,Br, OH, oxo, CF₃, CHF₂, CH₂F and SH or by one or more groups selectedfrom OR^(2.1), C₁₋₃-alkylene-OR^(2.1), SR^(2.1), SO—R^(2.1),SO₂—R^(2.1), COOR^(2.1), COR^(2.1), C₁₋₂-alkanol, C₃₋₁₀-cycloalkyl,phenyl, methyl, ethyl, propyl, isopropyl, phenyl-C₁₋₂-alkylene,hetaryl-C₁₋₂-alkylene, het, hetaryl, C₁₋₂-alkanol and NR^(2.2)R^(2.3),which in turn may optionally be substituted by one or more groupsselected from OH, OR^(2.1), oxo, F, Cl, Br, CF₃, CHF₂, CH₂F, C₁₋₆-alkyl,phenyl and NR^(2.2)R^(2.3), and wherein R³ is a group selected from asaturated or partly saturated, monocyclic three- to seven-memberedheterocyclic group, a saturated or partly saturated, bicyclic five- toeleven-membered heterocyclic group, a monocyclic, five- to six-memberedheteroaryl and a bicyclic, seven- to eleven-membered heteroaryl, whichcontains in each case 1, 2, 3 or 4 heteroatoms selected independently ofone another from N, O and S and which may optionally be substituted ineach case by one or more groups selected from halogen, C₁₋₃-fluoroalkyl,CN, OH, oxo, —C₁₋₆-alkyl, —O—R^(2.1), —COOR^(2.1), SO—R^(2.1),C₆₋₁₀-aryl, C₁₋₃-alkylene-C₆₋₁₀-aryl, —C₁₋₃-alkylene-NR^(2.2)R^(2.3),⁻NR^(2.2)R^(2.3), a C₃₋₁₀-cycloalkyl, a C₁₋₃-alkylene-C₃₋₁₀-cycloalkyl,het, a hetaryl, C₁₋₃-alkylene-hetaryl and C₁₋₃-alkylene-het, which inturn may optionally be substituted by one or more groups selected fromOH, halogen, —C₁₋₃-fluoroalkyl, C₁₋₆-alkyl, C₆₋₁₀-aryl, —COO(C₁₋₃-alkyl)and O—(C₁₋₃-alkyl), and wherein: R^(2.1) is H or a group selected frommethyl, ethyl, propyl, isopropyl, monocyclic C₃₋₇ cycloalkyl,phenyl-C₁₋₂-alkylene, hetaryl-C₁₋₂-alkylene, het-C₁₋₂-alkylene,C₃₋₇-cycloalkyl-C₁₋₂-alkylene, phenyl, hetaryl, and het, each optionallysubstituted by one or more groups selected from OH, halogen, methyl,ethyl, propyl, isopropyl, O-methyl, O-ethyl, O-propyl, O-isopropyl, andphenyl, R^(2.2) and R^(2.3) are each independently H or a group selectedfrom methyl, ethyl, propyl, isopropyl, monocyclic C₃₋₇ cycloalkyl,phenyl-C₁₋₃-alkylene, hetaryl-C₁₋₃-alkylene, phenyl, het, hetaryl,CO—NH₂, CO—NHCH₃, CON(CH₃)₂, SO₂—(C₁-C₂-alkyl), CO—R^(2.1), andCOOR^(2.1), each optionally substituted by one or more groups selectedfrom OH, F, Cl, Br, methyl, ethyl, propyl, isopropyl, phenyl, andCOOR^(2.1), het is a three- to seven-membered, monocyclic, saturated orpartly saturated heterocyclic group which contains 1, 2, or 3heteroatoms independently selected from N, S, or O, and hetaryl is afive- to six-membered, monocyclic, aromatic heteroaryl which contains 1,2, or 3 heteroatoms independently selected from N, S, or O.
 3. Themethod according to claim 1, wherein for the PDE4 inhibitor of formula1: R² is a group according to formula 3

wherein: R⁵ is OH or NH₂, and R⁴ is a group selected from C₁₋₄-alkyl,hetaryl, and phenyl, each of which is optionally substituted by one ormore groups selected from OH, F, Br, OR^(2.1), oxo, methyl, ethyl,C₁₋₂-alkanol, phenyl, COOR^(2.1), CH₂—NR^(2.2)R^(2.3), andNR^(2.2)R^(2.3).
 4. The method according to claim 1, wherein for thePDE4 inhibitor of formula 1, R⁴ is methyl, ethyl, propyl, or isopropyl.5. The method according to claim 1, wherein for the PDE4 inhibitor offormula 1: R² is a monocyclic three-, four-, five-, six-, orseven-membered cycloalkyl ring optionally substituted in the spiroposition by a group selected from —CH₂—OR^(2.1), branched or unbranchedC₂₋₆-alkylene-OR^(2.1), methyl, ethyl, propyl, isopropyl, butyl,isobutyl, cyclopropyl, —CF₃, CHF₂, CH₂F, and C₂₋₄-fluoroalkyl, whereinR^(2.1) is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.
 6. Themethod according to claim 1, wherein for the PDE4 inhibitor of formula1: R² is phenyl optionally substituted in one or both meta positions byone or more groups selected from methyl, ethyl, propyl, isopropyl,cyclopropyl, F, Cl, Br, OH, OR^(2.1), COOR^(2.1), CF₃, CHF₂, CH₂F, NH₂,and N(CH₃)₂, wherein R^(2.1) is H, methyl, or ethyl.
 7. The methodaccording to claim 1, wherein for the PDE4 inhibitor of formula 1: R² isa monocyclic, saturated three-, four-, five-, six-, or seven-memberedheterocyclic group with 1, 2, or 3 heteroatoms in each case selectedfrom N, O, and S, which is optionally substituted by one or more groupsselected from fluorine, chlorine, bromine, CF₃, CHF₂, CH₂F, OH, oxo, andSH or by one or more groups selected from OR^(2.1),C₁₋₃-alkylene-OR^(2.1), SR^(2.1), SO—R^(2.1), SO₂—R^(2.1), COOR^(2.1),COR^(2.1), C₁₋₆-alkanol, C₃₋₁₀-cycloalkyl, phenyl, C₁₋₆-alkyl,phenyl-C₁₋₆-alkylene, hetaryl-C₁₋₆-alkylene, het, hetaryl, andNR^(2.2)R^(2.3), each of which in turn is optionally substituted by oneor more groups selected from OH, OR^(2.1), oxo, F, Cl, CF₃, CHF₂, CH₂F,C₁₋₆-alkyl, phenyl, and NR^(2.2)R^(2.3).
 8. The method according toclaim 1, wherein for the PDE4 inhibitor of formula 1: R² is amonocyclic, saturated, six-membered heterocyclic group with a heteroatomselected from N, O, and S, which is optionally substituted by one ormore groups selected from F, Cl, Br, CF₃, CHF₂, CH₂F, OH, oxo, NH₂,NHCH₃, N(CH₃)₂, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy,and ethoxy.
 9. The method according to claim 1, wherein for the PDE4inhibitor of formula 1: R² is piperidine or tetrahydropyran, eachoptionally substituted by one or more groups selected from F, Cl, Br,OH, CF₃, CHF₂, CH₂F, NH₂, NHCH₃, N(CH₃)₂, oxo, methyl, and methoxy. 10.The method according to claim 1, wherein for the PDE4 inhibitor offormula 1: R³ is a monocyclic five- or six-membered heteroaryl ringoptionally substituted by one or more groups selected from F, Cl, Br,CF₃, CHF₂, CH₂F, CN, OH, -methyl, ethyl, propyl, isopropyl, —O-methyl,O-ethyl, —COOmethyl, —COOethyl, SO₂—(CH₃), SO—(CH₃), SO₂—(CH₂CH₃),SO—(CH₂CH₃), phenyl, -methylene-phenyl, -ethylene-phenyl, —NH₂,—NH(CH₃), N(CH₃)₂, -methylene-NH₂, -methylene-NH(CH₃),-methylene-N(CH₃)₂, C₃₋₆-cycloalkyl, methylene-C₃₋₆-cycloalkyl, asaturated or partly saturated, five- to six-membered heterocyclic group,a five- or six-membered heteroaryl, -methylene-hetaryl, and-methylene-het, each of which in turn is optionally substituted by oneor more groups selected from OH, F, Cl, Br, CF₃, CHF₂, CH₂F, methyl,ethyl, propyl, isopropyl, phenyl, —COO(CH₃), —O-methyl, and —O-ethyl.11. The method according to claim 1, wherein for the PDE4 inhibitor offormula 1: R³ is a bicyclic 9- to 11-membered saturated, unsaturated, orpartly saturated heterocyclic group optionally substituted by one ormore groups selected from F, Cl, Br, CF₃, CHF₂, CH₂F, CN, OH, -methyl,ethyl, propyl, isopropyl, —O-methyl, O-ethyl, —COOmethyl, —COOethyl,SO₂—(CH₃), SO—(CH₃), SO₂—(CH₂CH₃), SO—(CH₂CH₃), phenyl,-methylene-phenyl, -ethylene-phenyl, —NH₂, —NH(CH₃), N(CH₃)₂,-methylene-NH₂, -methylene-NH(CH₃), -methylene-N(CH₃)₂, C₃₋₆-cycloalkyl,methylene-C₃₋₆-cycloalkyl, a saturated, partly unsaturated, orunsaturated 5- to 6-membered heterocyclic group, a 5- to 6-memberedheteroaryl, -methylene-hetaryl, and -methylene-het, each of which inturn is optionally substituted by one or more groups selected from OH,F, Cl, Br, CF₃, CHF₂, CH₂F, methyl, ethyl, propyl, isopropyl, phenyl,—COO(CH₃), —O-methyl and —O-ethyl.
 12. The method according to claim 10,wherein for the PDE4 inhibitor of formula 1: R³ is pyrrole, pyrazole,furan, thiophene, thiazole, imidazole, oxazole, pyridazine, pyrimidine,pyrazine, thiadiazole, oxadiazole, triazine, isooxazole, isothiazole, orpyridine, each of which is optionally substituted by one or more groupsselected from F, Cl, Br, CF₃, CHF₂, CH₂F, -methyl, ethyl, propyl,isopropyl, —O-methyl, O-ethyl, —COOmethyl, —COOethyl, SO₂—(CH₃),SO₂—(CH₂CH₃), phenyl, -methylene-phenyl, -ethylene-phenyl, —NH₂,—NH(CH₃), N(CH₃)₂, -methylene-NH₂, -methylene-NH(CH₃),-methylene-N(CH₃)₂, C₃₋₆-cycloalkyl, methylene-C₃₋₆-cycloalkyl, het,hetaryl, -methylene-hetaryl, and -methylene-het, each of which in turnis optionally substituted by one or more groups selected from OH, F, Cl,Br, CF₃, CHF₂, CH₂F, methyl, ethyl, propyl, isopropyl, phenyl,—COO(CH₃), —O-methyl, and —O-ethyl.
 13. The method according to claim11, wherein for the PDE4 inhibitor of formula 1: R³ is benzoxazole,benzodioxole, dihydrobenzodioxin, benzodioxin, benzisoxazole,benzothiazole, benzisothiazole, thienopyrimidine, furopyrimidine,thienopyridine, furopyridine, indole, isoindole, quinoxaline,naphthyridine, pyridopyrazine, pyridopyrimidine, quinoline,isoquinoline, benzoimidazole,6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine, benzothiophene,benzofuran, quinazoline, indazole, isobenzofuran, or pteridine, each ofwhich is optionally substituted by one or more groups selected from F,Cl, Br, CF₃, CHF₂, CH₂F, CN, OH, -methyl, ethyl, propyl, isopropyl,—O-methyl, O-ethyl, —COOmethyl, —COOethyl, SO₂—(CH₃), SO₂—(CH₂CH₃),phenyl, -methylene-phenyl, -ethylene-phenyl, —NH₂, —NH(CH₃), N(CH₃)₂,-methylene-NH₂, -methylene-NH(CH₃), -methylene-N(CH₃)₂, C₃₋₆-cycloalkyl,methylene-C₃₋₆-cycloalkyl, het, hetaryl, -methylene-hetaryl, and-methylene-het, each of which in turn is optionally substituted by oneor more groups selected from OH, F, Cl, Br, CF₃, CHF₂, CH₂F, methyl,ethyl, propyl, isopropyl, phenyl, —COO(CH₃), —O-methyl, and —O-ethyl.14. The method according to claim 1, wherein for the PDE4 inhibitor offormula 1: R¹ is H; R² is a group selected from

and R³ is a group selected from


15. The method according to claim 1, wherein for the PDE4 inhibitor offormula 1 is selected from: 1.1(3-fluorophenyl)-[5-oxo-2-(4-thiazol-2-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-amine1.2(R)-3-methyl-2-[5-oxo-2-(4-thiazol-2-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-butan-1-ol1.3[2-(4-benzoxazol-2-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5λ□⁴-thieno[3,2-d]pyrimidin-4-yl]-(3-fluorophenyl)-amine1.4[2-(4-benzoxazol-2-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-(tetrahydropyran-4-yl)-amine1.5(R)-2-{2-[4-(6-chloropyridazin-3-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-3-methylbutan-1-ol1.6{2-[4-(6-chloropyridazin-3-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-(3-fluorophenyl)-amine1.7(R)-2-[2-(4-benzoxazol-2-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-3-methylbutan-1-ol1.8(1-{2-[4-(5-chloropyridin-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-cyclopropyl)-methanol1.9{2-[4-(5-chloropyridin-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-(tetrahydropyran-4-yl)-amine1.10{2-[4-(3-dimethylaminopyridazin-4-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-(3-fluorophenyl)-amine1.116-chloro-4-{4-[4-(3-fluorophenylamino)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-2-yl]-piperazin-1-yl}-pyridazin-3-ol1.122-{4-[6-(2-ethoxyethoxy)-pyridazin-3-yl]-piperazin-1-yl}-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl)-(3-fluorophenyl)-amine1.13(3-fluorophenyl)-[5-oxo-2-(4-pyridazin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-amine1.14(R)-2-{2-[4-(4-methoxy-1-methyl-1H-benzimidazol-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-3-methylbutan-1-ol1.15(R)-2-{2-[4-(7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepin-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-3-methylbutan-1-ol1.16(R)-3-methyl-2-[5-oxo-2-(4-pyrimidin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-butan-1-ol1.174-{4-[4-((R)-1-hydroxymethyl-2-methylpropylamino)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-2-yl]-piperazin-1-yl}-pyridin-2-ol1.18(R)-3-methyl-2-[5-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-butan-1-ol1.19(R)-2-{2-[4-(3-dimethylaminopyridazin-4-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-3-methylbutan-1-ol1.206-chloro-4-{4-[4-((R)-1-hydroxymethyl-2-methylpropylamino)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-2-yl]-piperazin-1-yl}-pyridazin-3-ol1.21(R)-2-(2-{4-[6-(2-ethoxyethoxy)-pyridazin-3-yl]-piperazin-1-yl}-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino)-3-methylbutan-1-ol1.22(R)-3-methyl-2-[5-oxo-2-(4-pyridazin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-butan-1-ol1.23{1-[5-oxo-2-(4-pyrimidin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-cyclopropyl}-methanol1.24{1-[5-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-cyclopropyl}-methanol1.25(S)-1-methyl-5-[5-oxo-2-(4-pyrimidin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-piperidin-2-one1.26{2-[4-(5-fluoro-1-methyl-1H-benzoimidazol-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-(tetrahydropyran-4-yl)-amine1.27[5-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-(tetrahydropyran-4-yl)-amine1.28(3-fluorophenyl)-{2-[4-(4-methoxy-1-methyl-1H-benzimidazol-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-amine1.29{2-[4-(7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepin-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-(3-fluorophenyl)-amine1.30(3-fluorophenyl)-[5-oxo-2-(4-pyrimidin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-amine1.314-{4-[4-(3-fluorophenylamino)-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-2-yl]-piperazin-1-yl}-pyridin-2-ol1.32(3-fluorophenyl)-[5-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl]-amine1.33(3-fluorophenyl)-(2-{4-[4-(4-fluorophenyl)-thiazol-2-yl]-piperazin-1-yl}-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl)-amine1.34[2-(4-benzo[d]isoxazol-3-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-(3-fluorophenyl)-amine1.35(R)-2-(2-{4-[4-(4-fluorophenyl)-thiazol-2-yl]-piperazin-1-yl}-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino)-3-methylbutan-1-ol(R)-2-[2-(4-benzo[d]isoxazol-3-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-3-methylbutan-1-ol.16. The method according to claim 1, wherein for the NSAID is a COX1-inhibitor or COX 2-inhibitor.
 17. The method according to claim 16,wherein the NSAID is selected from aceclofenac (2.1), acemetacin (2.2),acetylsalicylic acid (2.3), alclofenac (2.4), alminoprofen (2.5),amfenac (2.6), ampiroxicam (2.7), antolmetinguacil (2.8), anirolac(2.9), antrafenine (2.10), azapropazone (2.11), benorilate (2.12),bermoprofen (2.13), bindarit (2.14), bromfenac (2.15), bucloxinic acid(2.16), bucolom (2.17), bufexamac (2.18), bumadizone (2.19), butibufen(2.20), butixirate (2.21), carbasalate calcium (2.22), carprofen (2.23),choline magnesium trisalicylate (2.24), celecoxib (2.25), cinmetacin(2.26), cinnoxicam (2.27), clidanac (2.28), clobuzarit (2.29), deboxamet(2.30), dexibuprofen (2.31), dexketoprofen (2.32), diclofenac (2.33),diflunisal (2.34), droxicam (2.35), eltenac (2.36), enfenamic acid(2.37), etersalate (2.38), etodolac (2.39), etofenamat (2.40),etoricoxib (2.41), feclobuzon (2.42), felbinac (2.43), fenbufen (2.44),fenclofenac (2.45), fenoprofen (2.46), fentiazac (2.47), fepradinol(2.48), feprazone (2.49), flobufen (2.50), floctafenin (2.51),flufenamic acid (2.52), flufenisal (2.53), flunoxaprofen (2.54),flurbiprofen (2.55), flurbiprofenaxetil (2.56), furofenac (2.57),furprofen (2.58), glucametacin (2.59), ibufenac (2.60), ibuprofen(2.61), indobufen (2.62), indometacin (2.63), indometacinfarnesil(2.64), indoprofen (2.65), isoxepac (2.66), isoxicam (2.67), ketoprofen(2.68), ketorolac (2.69), lobenzarit (2.70), lonazolac (2.71),lornoxicam (2.72), loxoprofen (2.73), lumiracoxib (2.74), meclofenamicacid (2.75), meclofen, mefenamic acid (2.76), meloxicam (2.77),mesalazin (2.78), miroprofen (2.79), mofezolac (2.80), nabumetone(2.81), naproxen (2.82), nifluminic acid (2.83), olsalazine (2.84),oxaprozin (2.85), oxipinac (2.86), oxyphenbutazone (2.87), parecoxib(2.88), phenylbutazone (2.89), pelubiprofen (2.90), pimeprofen (2.91),pirazolac (2.92), priroxicam (2.93), pirprofen (2.94), pranoprofen(2.95), prifelon (2.96), prinomod (2.97), proglumetacin (2.98),proquazone (2.99), protizinic acid (2.100), rofecoxib (2.101), romazarit(2.102), salicylamide (2.103), salicylic acid (2.104), salmistein(2.105), salnacedin (2.106), salsalate (2.107), sulindac (2.108),sudoxicam (2.109), suprofen (2.110), talniflumat (2.111), tenidap(2.112), tenosal (2.113), tenoxicam (2.114), tepoxalin (2.115),tiaprofenic acid (2.116), taramide (2.117), tilnoprofenarbamel (2.118),timegadine (2.119), tinoridine (2.120), tiopinac (2.121), tolfenamicacid (2.122), tolmetin (2.123), ufenamate (2.124), valdecoxib (2.125),ximoprofen (2.126), zaltoprofen (2.127), and zoliprofen (2.128).
 18. Themethod according to claim 17, wherein the NSAID is selected fromcelecoxib (2.25), etoricoxib (2.41), lumiracoxib (2.74), parecoxib(2.88), rofecoxib (2.101), and valdecoxib (2.125).
 19. The methodaccording to claim 18, wherein the NSAID is selected fromacetylsalicylic acid (2.3), celecoxib (2.25), diclofenac (2.33),ibuprofen (2.61), indometacin (2.63), lumiracoxib (2.74), meloxicam(2.77), naproxen (2.82), and priroxicam (2.93).
 20. The method accordingto claim 19, wherein the NSAID is selected from acetylsalicylic acid(2.3), diclofenac (2.33), meloxicam (2.77), naproxen (2.82), andibuprofen (2.61).
 21. The method according to claim 20, wherein the PDE4inhibitor is administered in a single dose of 0.01 mg to 50 mg.
 22. Themethod according to claim 21, wherein the NSAID is administered asfollows: acetylsalicylic acid (2.3) in a single dose of 50 to 2000 mg,diclofenac (2.33) in a single dose of 25 mg to 150 mg, meloxicam (2.77)in a single dose of 7.5 mg to 30 mg, naproxen in a single dose of 250 to1000 mg, or ibuprofen in a single dose of 200 to 2400 mg.
 23. The methodaccording to claim 1, wherein the disease is COPD, chronic sinusitis,asthma, Crohn's disease, idiopathic pulmonary fibrosis, or ulcerativecolitis.
 24. The method according to claim 1, wherein the PDE4 inhibitorand the NSAID are administered in two separate formulations within atime interval of 0 to 6 hours.
 25. The method according to claim 24,wherein the formulation containing the PDE4 inhibitor is an oral orinhalative formulation, and the formulation containing the NSAID is anoral formulation.